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CLINICAL PHARMACOKINETICS IN SPECIAL POPULATIONS ern Pharmacokinet. 2Q(5): 341-369. 19950312-5963/95/00 11-0341/$14.50/0
© Ads Kiterncrtioool l imited . ADrightsreserved
Clinical Pharmacokinetics ofAntiepileptic Drugs in Paediatric PatientsPart II. Phenytoin, Carbamazepine, Sulthiame, Lamotrigine,Vigabatrin, Oxcarbazepine and Felbamate
Dina Battino, Margherita Estienne and Giuliano Avanzini
Neurological Institute Carlo Besta, Milan, Italy
Contents. . . 341
· 342· 343· 345
. . . . . . . . . . 347. . . . . . . 348
· 351352
· 352· 353· 357. 360· 361
. . 362· 362· 362
362· 362· 363· 363
363364364364365365
· 365
Summary .1. Phenytoin . . . . . . . . . . . . . . .
1.1 Absorption and Bioavailabillty1.2 Distribut ion and Protein Binding . . . . . . .1.3 Metabolism . . . . . . . . . . . . . . . . . . . .1.4 Elimination . . . . . . . . . . . . . .1.5 Therapeutic Implications of Pharmacokinetic Properties
2. Carbamazepine . . . . . . . . . . . .2.1 Absorption and Bioavailability .2.2 Distribution and Protein Binding .2.3 Metabolism .2.4 Elimination .2.5 Therapeutic Implications of Pharmacokinetic Properties
3. Sulthiame . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4. New Antiepileptic Drugs. . . . . . .
4.1 lamotrigine . . .4.1.1 Absorption . . . . . . . .4.1.2 Elimination . . . . . . . . . . . . . .4.1.3 Relationship Between Dose/Kilogram and Plasma Concentrations
4.2 Vigabatrin . . . . . . . . . . . . . . . .4.2.1 Absorption and Bioavailabllity .4.2.2 Distribution . . . . . . . . . . . .4.2.3 Elimination . . . . . . . . . . . .4.2.4 Therapeutic Implications of Pharmacokinetic Properties
4.3 Oxcarbazepine . . .4.4 Felbamate .
5. Conclusion .
Summary Thi s article is the second part of a review of the pharmacokinetics of antiepilepti c dru gs (AEDs) in paediatric patients . It reviews 139 papers publi shed since1969 on the pharmacokinetics of phen ytoin , carbamazepine, sulthiame, lamotrigine (phenyltriazine), vigabatrin, oxcarbazep ine and felbamate in this popul at ion .
The pharm acokinetics of phenytoin are significa ntly affected by age. The termin al elimination half-life (t '/2Z) is relati vely long in neon ates; it then decreases
342 Battinoet al.
during the first postnatal month to lower values than in adults, and then progressively increases with age due to an age-dependent decrease in the metabolic rate.Rate of elimination is strongly dose-dependent at all ages. The combination ofthese factors makes it difficult to predict what plasma concentrations would resultfrom dose per kilogram (doselkg) adjustments in neonates and children, especially when phenytoin is coadministered with other liver enzyme-inducing drugs,such as phenobarbital and carbamazepine . The concentration of phenytoin inbrain and other tissues depends on the unbound/total concentration ratio. Forneonates this ratio is higher than that found in adults; it then decreases over thefirst 3 postnatal months to approach adult values. The fraction of unbound phenytoin is significantly higher in patients also receiving valproic acid.
Carbamazepine is almost completely epoxidised to the active metabolitecarbamazepine epoxide, which is in turn converted to carbamazepine diol. Metabolic conversion of carbamazepine and renal clearance of carbamazepine diolare much higher in children than in adults; t1/zzof carbamazepine is thus very shortin young children, increasing with age. No data are available on the neonatalperiod. The carbamazepine epoxide/carbamazepine ratio may be significantlyincreased by metabolic inducers (e.g. phenytoin, phenobarbital and primidone)or by inhibitors of the carbamazepine epoxide to carbamazepine diol conversion(e.g. valproic acid). Macrolides inhibit carbamazepine metabolism, thus increasing carbamazepine plasma concentrations . Drug-induced changes in carbamazepine kinetics are particularly pronounced in children.
In children, a higher doselkg of sulthiame, lamotrigine, oxcarbazepine andfelbamate than in adults is required to obtain an effective plasma concentration.The published data do not support the use of a different dose/kg of vigabatrin inchildren aged between I month and 15 years.
The pharmacokinetic information in the paediatric literature may help in assessing AED prescriptions in childhood to prevent seizures and AED-relatedadverse effects on the ongoing maturational processes of the brain.
This is the second part of a review of the pharmacokinetics of antiepileptic drugs (AEDs) in paediatric patients. The first part[1ldeals with the pharmacokinetics of phenobarbital, prirnidone, valproicacid, ethosuximide and mesuximide (rnethsuximide) . This second part covers phenytoin, carbamazepine, sulthiame and the new AEDs for whichpharmacokinetic data in children are available lamotrigine (phenyltriazine), vigabatrin, oxcarbazepine and felbamate.
139 original papers published since 1969 havebeen reviewed here. The papers selected for reviewwere mostly dedicated to paediatric case seriesalone; studies based on mixed adult-and-childrenseries were included only when the reporting ofindividual data made it possible to analy se the pae-
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diatric data separately. Data on neonates were included only when AEDs were administered afterbirth; data on transplacental exposure were therefore excluded.
The aims and methods used in this review havebeen described in Part 1.[1]
1. Phenytoin
Phenytoin is one of the oldest anticonvulsantdrugs available, having been introduced in 1938 byMerrit and Putnam. Its pharmacokinetics are characterised by a capacity-limited metabolism: thedrug-metabolising enzymes may be readily saturated as plasma drug concentrations rise. In somepatients, this saturation may occur even at phenytoin plasma concentrations within the therapeutic
Clin. Phormocok inet . 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
range. Once the enzymes are saturated, accumulation of phenytoin occurs and, under these conditions,steady-state plasma concentrations of phenytoinincrease disproportionately to an increase in doseper kilogram (dose/kg).
Consequently, it is often difficult to obtain thedesired plasma concentration of phenytoin: at lowplasma concentrations elimination of the drug maybe high, but beyond the saturation point (whichvaries greatly from individual to individual) evena small dose/kg increase may lead to a substantialrise in plasma concentrations.
1.1 Absorption and Bioavailability
Phenytoin may be administered orally, intramuscularly, rectally or intravenously (no data concerning its rectal administration in children areavailable).
After oral doses of phenytoin, a wide range ofplasma concentrations are encountered in neonates,infants and children (table I). In patients givenmean intravenous loading doses of phenytoin 5 to33 mg/kg, mean plasma concentrations of 2 to 19mg/L are reached after 2 hours; oral loading dosesof 10 mg/kg lead to mean plasma concentrations ofabout 7 mg/L after 2 hours (table I).
Phenytoin plasma concentrations can be verylow in children (particularly in the youngest patients - see table I), one of the proposed explanations being inadequate absorption.P-!" However,data published by Leff et alP] indicate that gastrointestinal absorption is not impaired in newbornsand in infants aged less than 2 months: they foundthat the total recovery of phenytoin and its metabolites in the stool and urine of infants receivingoral phenytoin is similar to that of children and ofadults after intravenous administration.
Absorption is increased when oral phenytoin isadministered together with food; in infancy the influence of food is more pronounced than in olderchildren. The mean area under the phenytoin plasmaconcentration-time curve (AVC) was found to increase with concomitant ingestion of food by 47,26 and 13%, respectively, during the first year oflife, in children aged 1 to 6 years, and in children
© Adis International Limited. All rights reserved.
343
aged 7 to 18 years. In the same age groups, themean time to maximum concentration (tmax) wasdecreased by 69, 29 and 21%, respectively, whenfood was co-ingested.Uf
Enteral feeding may interfere with the absorption of oral phenytoin: very low plasma concentrations were observed in 2 children (aged 5 and 13years) who were receiving enteral feeding, despiteadequate dosage; higher plasma concentrationswere attained when the feeds were stopped or whenintravenous phenytoin was used.[15] Phenytoin suspension is a weak acid, dissolving best under alkaline conditions; enteral feeding may affect the absorption of phenytoin by lowering intestinal pH(thus increasing the un-ionised fraction) or becauseof formation of complexes with feed components.Another possible explanation is a loss of phenytointo the walls ofnasogastric feeding tubes (unless thetubes are irrigated after drug delivery).
Differences in the bioavailability of differentphenytoin formulations are well documented. Thesuspension has better absorption than capsules.Ufcapsules have better absorption than tablets;[17-19]and tablets have better absorption than powder(probably as a result of their lower particle size andconsequently higher dissolution rate)pO,21] Thedifference in bioavailability between tablets andpowder is greater in children than in adults.[20]
The rate and extent of absorption may also varybetween the tablets or powder of different manufacturers.[19,21] Moreover, different strengths of thesame formulation may have different absorptionrates. Data published by Manson et aU 13] (see tableI) indicate that phenytoin plasma concentrationsare significantly higher with 100mg capsules thanwith 100mg tablets, but this situation is reversedwhen 30mg capsules are compared with 30mg tablets. The authors attributed these results to greaterdifferences in dissolution between 100mg and30mg capsules.
At steady-state, phenytoin plasma concentrations shoe moderate fluctuations; the intrapatientday-to-day variation calculated from 5 predosemorning samples in 10 children aged 6 to 15 yearsvaried from 9 to 33%, with a mean of 19%P2]
Ciin. Pharmacokinet. 29 (5) 1995
e TableI. Plasma concentrations and C/O ratios of phenytoin in paed iatric patients I t»a.",. Reference Number Age group Dose Associated Cma, Cmin Cmean C(2h) C(6h) C(12h) C/D
~ of pts (mg/kg) therapy (mglL) (mg/L) (mglL) (mg/L) (mg/L) (mg/L)
3 [route]0s Sin gle dose::JQ. Alban; et al.12]o 12 <l y 10 ±2[IV) 9.6±4.1 0.9 ± 004c3 11 1-6y B±3(IV] 4.7±3.1 0.7±0.6i 12 7-1By 5 ± 2 [IV] 2.6 ± 0.6 0.6±0.3o,~ 3 <l y 10±0[IV] 9A± 1.3 0.9 ±0.1
<8' 4 1-6y 7±1 [IV) 9.6 ± 1.6 1.3±0.2zr;;r 11 7-18y 6±2[IV) 2.3 ± 004 0.5 ± 0.2ib Albani[3la 5 6 ±7wk 33 ± 5 [IV)b 13.2 ± 4.6' 004± 0.1(1)< 10 6 ±3y 31 ± 9 [IV]b 21.7 ± 9.7' 0.7 ± 0.3s
Riviello et al.141 20 3 ± 4y 18 (IV] 19.1 ±5.0 15.7 ± 4A 13.5 ± 4.6
Buchanan et 5 5-7y 10 [PO] No 6.6 ± 3.8d 8.8 ± 1.6" 6.2 ± 1.1'·9al.[51 5 5-7y 10 [POJ PB 2A±1.7d 3.2 ± 2.5" 2.6 ± 1.8'
Single dose followedby maintenance dosePainter et al.[6] 21 T/P 10-22 [IV) PB 14.5 ± 3.0
Loughnan et 8 T/P <lwk 8 (POJ PB 11.0 ± 9.6""al.(7] 10 2-4wk 8 ±1 [POI PB 2.2 ± 1.2""
9 T/P 5-96wk 8 ±1 [POI PB 2.0 ± 1.5Jailing et al.[8] 4 3-7Bd 10±1 [1M] No/yes 5.1 ± 3.6
6 3-7Bd 11± 4 [PO) No/yes 2.9 ± 1.6Left et al[9] 7 1-9wk B ± 4 [IV/PO) PB 4.8 ±4.6 0.6 ± 0.5
Steady-stateAman et al.Po/ 11 7 ± 2y 7±2 [POl No 1.1 ± 0.6b.; 0.7 ± OAb 0.9 ± 0.5b
Oodsonl'" 19 6 ±6y 8±4[PO] No/yes 10.7 ± 6.2 B.0 ±5.1 9.2 ± 504 t.l ±0.6Albani et al[2]a 12 <l y 12±6 [PO] No 904± 3.9 1.0±0.6
11 1-6y 11± 5 [POj No 13.7 ± 3.B 1.5±0.7
12 7-18y 15 ±5[POJ No 14.9± 5.1 2.9± 1.4
3 <ly 16 ±2 [PO) Yes 14.8 ± 6.9 0.9 ±0.5
4 1-6y 12 ±7[POJ Yes 16.3 ± 2.6 1.7±1.0Q 11 7-18y 6±1 [POI Yes 16.1 ± 504 2.6± 1.1S'
Albanii3]a 31"U 9 ±lwk 22±4 [POj 12.2 ±5.9 0.6±0.3::r
9' 6 ± 3y 14±7[POj 17.8 ±3.9 1.5±0.7
~ Leppick et a1.112] 7' 10 ± 3y 7 ±3 [POl Yes 16.7 ± 4.5""" 204± 0.9
0 7m 10 ±3y 7±3 [PO] Yes 8.2 ± 3.6 1.1 ±0.5""~. Manson et a1.113) 13 13 ±2y (5 ± 2) x 100mg caps (PO) Yes 8.1 ± 5.9" 1.5 ± 0.7 OJ:+ ~~ 5 13 ±2y (5 ± 2) x 100mg labs [PO) Yes 5.3 ± 4.7 0.9±0.6 g'§ 13 9 ±3y (3 ± 1) x 30mg caps [PO) Yes 1.1 ±OS" 004± 0.2
~ 5 Yes 0.7 ± 0.5~
9 ±3y (3 ± 1) x 30mg tabs [PO) 2.3± 104 f2..r.n
Antiepileptic Drugs in Paediatric Patients (II)
© Adis International Limited. All rights reserved.
345
The percentage change in daily fluctuation ofplasma concentration [calculated as the differencebetween maximum plasma concentration (Cmax)
and minimum plasma concentration (Cmin) , divided by the mean plasma concentration (Cmean)
for the day] is smaller in children receiving oralphenytoin twice a day than once a day (mean percentages of change are 46 and 68%, respectively),[IO] and smaller also with capsules ratherthan suspension (10% versus 52%»)10]
At higher concentrations, fluctuations are alsosmaller.l'U because plasma drug concentrationsdecline more slowly as a result of the capacity-limited metabolism of phenytoin.
When phenytoin is administered orally twice aday, the plasma concentrations measured 8 hourspostdose are the most reliable indication of theaverage 12-hour postdose concentration; however,predose morning samples also correlate well withaverage steady-state concentrations)"]
Data concerning intramuscular administrationin children are very scarce, making it impossibleto drawn any definite conclusions (table I). However, JaIling et aU 8] have reported higher plasmaconcentrations after intramuscular than after oraladministration of phenytoin in the same group ofchildren.
1.2 Distribution and Protein Binding
Following absorption, phenytoin distributesfreely in the body; mean apparent volume of distribution (VIF) based on total plasma concentrations averages about 0.2 to 1.2 L/kg (table II).
In neonates, V/F is not affected by gestational[6,23] or postnatal age,[23] and is similar to thatof infants aged less than 3 months.Pl
Brain concentrations of phenytoin, reported asbeing 89 to 128% of their respective plasma concentrations,[32-34] are linearly related to plasmaconcentrations'P' and, in neonates, are not affectedby gestational age or duration of treatment.P'J Theratio between grey and white matter concentrationsvaries from 0.78 to 1.74.[33,34]
The tissue/plasma concentration ratios of phenytoin for liver, heart and muscle are higher than that
Ciin. Pharmacokinet. 29 (5) 1995
346 Battinoet al.
Table II. Phenytoin pharmacokinetic parameters in paediatric patients
Reference Number Age group Dose (mglkg) Associated Cmax
of pts [route] therapy (mg/L)t1,;,
(h)V/F(Ukg)
Vmax Km(mg/kg/day) (mg/L)
Single doseLoughnan et 4al.17J 6
7
PT<lwkT2-96wk
12 [IV]12 [IV]
12 [IV]
No
PBPB
75.4 ± 64.5 0.8 ± 0.2a
20.7 ± 11.6" 0.8 ± 0.3 NS7.6 ± 3.5 0.7 ± 0.2
5.2±2.1
4.5±2.2
3.9±1.6
1.7±0.5
10.4 ± 3.7
12.0±2.3
5.3±0.9
17.9±5.7
0.7-1.0
0.2-0.6
1.00.4-0.70.4-0.6
0.8±0.4
1.2 ±0.11.2 ± 0.21.2±0.2
0.9±0.3c
9.6±4.5f
31.8 ±4.0f
17.8 ± 4.79
23.7 ±3.89
10.6 ± 4.49
23.8± 3.39
104.0± 17.018.6±7.492.2-6.4
1.6-3.7
16.11.6-4.21.2-6.75.3±0.ge
33.7±35.757.3 ± 48.2
10.4 ± 4.238.6±3.9
7.2 ± 1.719.7±1.3
5.018.05.0
18.05.0
18.0
44-76
26.014.5±2.5
18.0
5.018.0
5.018.0
PB
PBPBNo/yes
No/yes
No/yes
7 T/P>3, <5wk 20 [IV/PO] No/yes
9 T/P 5 [IV) PB8 7mo-5y 5 [PO] No/yes2 <ly 1-5 [IV) No/yes
3 2-3y 1-5 [IV] No/yes1 3-4y 1-5 [IV] No/yes
3 4-5y 1-5 [IV] No/yes2 6-7y 1-5 [IV] No/yes4 6-10y 6-19 [PO]d No/yes
9 2mo-ly 6-19 [PO] No/yes
8 1-4y 6-19 [PO] No/yes
9 4-8y 6-19 [PO] No/yes
1610
13
Garretlson &JuskO[2SJDodson[27J
Steady-statePainter et al.lsJ
Dodson[24J
Curless etal.125J
Single dose followed by maintenance dosePainter et al.lsJ 16b P,gest wk 27-30 10-22 [IV]
P,gest wk 31-36 10-22 [IV]
T 10-22 [IV]T/P 2-36d 20 [IV/PO]T/P gjd 20 [IV/PO]
T/P 9-21d 20 [IV/PO]
Bourgeois &Dodson[23J
Bauer &Blouin[30I
14
11Koren et al.l28J 13Chiba et al.l29J 34
24
24224228
3332
Blain et al.[31J 40
21
8-12y12-16y
9±4y6mo-3y4-6y
7-9y10-16y2± ly5± ly
8± ly13±2y8mo-3y
Adults
6-19 [PO]6-19 [PO][PO]14±4[PO]11±3[PO]9±1 [PO]8±2[PO][PO]
[PO][PO][PO]
2-5 [PO]2-5 [PO]
No/yesNo/yes
YesNo/yes
No/yesNo/yes
NoNoNo
NoNo
No
11.1 ±3.07.9±2.312.3 ± 4.4
13.8±4.311.2 ± 3.09.5 ± 1.58.0± 1.714.0 ±4.3"10.9±3.0 NS
10.1 ±2.6"8.3±2.8
20.4 ± 2.1""8.7±0.7
5.7 ± 4.55.1 ±4.1
6.3±5.74.1 ±5.64.1 ±3.63.6 ± 4.13.0 ± 2.56.6±4.2NS
6.8±3.5NS6.5±3.9NS5.7±2.7
7.5±1.2NS9.4 + 2.3
a Calculated in 3 pts,b All patients.c Only for IV administration.d Overdosed children.e Minimum t1,;, when plasma concentration is much less than KmN.f Data reported by Bourgeois and Dodson,[25Jconcerning 8 children.g Data reported by Bourgeois and Dodson,[25J concerning 7 children.Abbreviationsandsymbols:Cmax= maximum plasma drug concentration;d = day(s); gest wk = gestationalweeks; IV= intravenous;Km = MichaelisMenten constant; mo = month(s); NS = nonsignificant value; P = premature; PB = phenobarbital; PO = oral; pts = patients; T = full termneonates; t1,;, = half-life; V/F = apparent volume of distribution; Vmax = maximum rate of metabolism; wk = week(s); " p < 0.01 vs followingrow; "" p < 0.001 vs following row.
© Adis International Limited. All rights reserved. elin. Pharmacokinet. 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
for grey/white matter, being 2.9 ±0.8 ,9.1 ±0.1 and3.4 ± 1.4, respectively, in 5 neonates.P" In a 6year-old child who died while receiving a numberof AEDs, the phenytoin liver concentration was 3.8times higher than the plasma concentration.Pf
In its free acid form, phenytoin also distributesinto all fluids . During the first 6 hours after an intravenous injection of phenytoin 10 to 20 mg/kg,cerebrospinal fluid (CSF) concentrations werefound to be greater than 2 mg/L, with a CSF/plasmaconcentration ratio ranging between 0.07 and0.28)35,36)
The CSF/plasma concentration ratio of phenytoin increases significantly over the first 8 hoursafter administration as the plasma concentrationdecreases; this phenomenon is consistent with the2-compartment model , according to which phenytoin is distributed from a central compartment(blood) into a peripheral compartment (CSF).136) Atsteady-state, phenytoin CSF concentrations of 2.4mg/L and 2.3 mg/L, respectively, were measuredin 2 children (aged 6 and 2 years) with plasma concentrations of 17.1 mg/L and 21.3 mg/L .137]
The CSF/plasma concentration ratio clo selyresembles the unbound/total plasma concentrationratio (table III), indicating that free phenytoin passively enters the CSF.
Phenytoin is largely bound to plasma proteins(table III). A close correlation between unboundand total plasma concentrations has been found bysome ,l22,43) but not all,l44] researchers.lv'l moreover, very stable individual free fraction levelshave been observed during daytime.F'l
Neonates have a more variable, and lower, level.of protein binding of phenytoin than do older children; phenytoin free fractions approach adult values by the age of 3 months,l7,38,45-48] The data reported in table III are consistent with the absenceof any age-related changes during childhood.
Hyperbilirubinaemia further decreases phenytoin protein binding in neonates,145,46) probably asa result of competition between endogenous bilirubin and phenytoin.
The phenytoin free fraction is more variable,and significantly higher, in patients receiving con-
© Adi s International Umited. All righ ts reserved.
347
comitant valproic acid than in those receivingmonotherapy or combination therapy with AEDsother than valproic acid (table III). In vitro valproicacid plasma concentrations linearly correlate withphenytoin free fraction s (statistically significant,r = 0.97); the same trend was observed in vivo (although not to a statistically significant level).I43)
Phenytoin protein binding is not affected by otherAEDs, tested in vitro.l431
The correlation between phenytoin saliva concentrations and unboundI39,41,44] or total plasmaconcentrationst-?' is considered excellent bymost,l39,41,42,44) but not all,l40,49] researchers.
The percentage change in daily fluctuation ofunbound phenytoin plasma concentrations doesnot significantly differ according to the number ofdaily doses, being 42% with once-daily administration , 24% with twice-daily administration and43% with administration three times daily.149J
Phenytoin concentrations in urine , which havebeen studied in a population of children andadults, ISO) are generally greater than free plasmaconcentrations; however, the correlation betweenthe two is close and is not influenced by age, urinepH or flow rate.150]
1.3 Metabolism
Elimination of phenytoin occurs largely via a hepatic microsomal mixed-function oxidase reaction,with subsequent glucuronidation and excretion ofthe hydroxylated derivatives, mainly p-hydroxyphenylhydantoin (HPPH). Minor metabolites include a dihydrodiol and trace amounts of a catecholand 3-0H-methylcatechol (CAT); both HPPH andCAT are predominantly found (>95%) in the conjugated form ,l91
Neonates can also conjugate hydroxylated metabolites with glucuronic acid; after the administration of phenytoin, free and conjugated HPPHwere identified in a number of urine samples collected 5 to 8 days after birth.l51] The extent andpattern of the excretion of phenytoin metabolitesdo not show any age-related changes, either between children of different ages or with respect toadults ,19.37.52]
Clin. Phormocokinet. 29(5) 1995
348 Battino et aI.
Table III. Phenytoin free fracti on and saliva/p lasma ratio in paediatric patients
Reference No. ofpts Age group Dose Measurement Associated Free fraction Stimulation Saliva/plasma Plasma(samples) (y) (mg/kg) method therapy (%) ratio conc.
(%) (mgl L)
Painter et 16 TIP 9-33 Ultrafiltration, 9.0-39.0al.[38) Centrifree tube
(Amicon®j
Ufshitz at 16(23) 1-15 6 ±1 Ultrafiltration. No/yes 7.8 ± 1.1 Yes 10.5± 1.1...a
al.(39) Cantrifree tube(Amicon®)
Zyssat et 22 (30) 6-15 No Yes 11.0al.(40]
Goldsmith (57) 0.5 -18 Yes 12.0 ±4.0& Ouvrierl41J
Friedman et 10 (12) 9-18 9.3al.[42J
Johno at (46) 1-15 2-30 EMI~ FreeLevel VPA 7.7 (5.7-9.0)'al.[43J system
(16) 1-15 2-30 VPA 12.4(9.3-16 .3)
Bachmann 29 (46) 9.5 ± 3b Ultraf iltration . NotVPA 9.2 t 1.8" Yes 1.1 to.1 c
et al.(44) Centrifree tube(Amicon®j
5(8) VPA 13.2 ±4.5
Leppick et ]d 1O± 3 7 ±3 EMil'"' Worthington Yes 14.9 ±3.8 16.7 t4.5al.(12J filter
7° 10±3 7 ±3 Yes 15.3±1 .6 8.2±3.6
a Versusfree fractio n.b All patie nts.c Ratio of salivary ultrafiltrate to plasma ultrafiltrate.d Baseline.e Febrile illness.Abbreviations and symbols: conc. = concentration ; EMI~ = commercially available enzyme multiplied immunoassay kit; P = premature infants;pts = patients; T = full term neonates; VPA = valproic acid; , p < 0.01 vs following row ; " p < 0.001 vs following row, unless otherwise specif ied.
HPPH appears in the plasma from the very beginning of phenytoin therapy and, in most cases,follow s in parallel the concentration of the parentdrug ; in some children, a plateau in HPPH plasmaconcentrations has been observed as the plasmaconcentrations of the parent drug rise , suggestinglimited metabolite formation at higher plasma drugconcentration s.F'J
Upon discontinuation oftherapy, plasma phenytoin concentrations fall by about 66% over 12 to 24hours, before any decline in plasma metabolite concentrations is discernible. Consequently, the HPPWphenytoin plasma concentration ratio increa ses;[53]the time course of the metabolite/parent drug ratiosreflects the presence of saturation kinetics .
At steady-state, the HPPHlphenytoin plasmaconcentration ratio shows a considerable interindi-
© Ad is International Limited . All right s reserved .
vidual variability[531 even among patients with similar phenytoin pla smaconcentrations.U'J HPPHplasma concentrations vary from 0.5 to 4.2% (unconjugated) and from U.8 to 49.9% (conjugated)of phenytoin plasma concentrations.P'"
It has been suggested that genetic factor s mayplaya role in determining this variability.Pl Slowand fast phenytoin metabolisers have been identified in children, irrespective of their age or theplasma concentrations of the parent drug ,l21
1.4 Elimination
1.4. 1ExcretionPhenytoin is excreted in urine mainly as meta
bolites; onl y I to 5% is excreted in an unmetabolised form.l9•521Data concerning the excretionof phenytoin as HPPH are summarised in table IV.
Clin. Pharmo cokinet. 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
The mean daily urinary excretion of phenytoinand its metabolites is about 50 to 88% of the dailydose, individual values ranging between 27 to91 %.19,12,37,52]
A diurnal pattern of HPPH excretion has beenshown in 3 patients,[26] excretion occurring mostlyduring the daylight hours; this may be the result ofa circadian variation in either the biotransformation or renal excretion of HPPH,
After the sudden cessation of phenytoin administered at a dosage of 18 mg/kg, the drug was nearlytotally excreted in 7 days;[37] the excretion ofHPPH remained relatively constant during the timethat plasma phenytoin concentrations fellp6]
Trace quantities of phenytoin and its metabolites are found in faeces.J?'
1.4.2Pharmacokinetics of EliminationThe nonlinear elimination of phenytoin has
been demonstrated in paediatric patients in a number of ways.
First, the relationship between dose/kg andplasma concentrations of phenytoin is nonlinear.[37,54,55] Secondly, the concentration dependence of the elimination of phenytoin has been welldocumented in children of all ages: in full term and
349
premature newborns, plasma terminal eliminationhalf-life (tY2Z) significantly increases with increasing plasma concentrationsl-Vf and, accordingly,
v/2Zsignificantly decreases when plasma concentrations decrease. In children with overdose, adecrease in t'/2Zfrom values as high as 532 hoursto 16 hours, with plasma concentrations decreasing from about 60 to 6 mg/L, has been reported. [24,26,56,57]
Furthermore, there is a clear-cut inverse correlation between both dose/kg and phenytoin plasmaconcentrations and the HPPH/phenytoin ratio inurine.F' this again indicates the concentrationdependent metabolic capacity of the enzyme.
Another approach demonstrating the nonlinearpharmacokinetics of phenytoin in children is basedon Michaelis-Menten kinetics,[29,58.61] as appliedto paediatric patientsP6.29,31,52,62.64] This model is
capable of predicting plasma drug concentrations,on the basis of the given dose/kg, the maximumrate of metabolism (Vmax) and the MichaelisMenten constant (Km) [equal to the plasma concentration in mg/L at which the metabolic rate isone-half of Vmax].
Table IV. Phenytoin excretion as p-hydroxyphenylhydantoin (HPPH) in paediatric patients
Reference Number of Age group Dose (mg/kg) Associatedpatients [route] therapy
HPPH/phenytoin HPPH excretedconcentration ratio (%)
HPPH/phenytoin urine concentration ratioAlbani et al.[21 12 <ly
11 1-6y
12 7-18y
3 <ly
4 1-6y
11 7-18y
10 ±2 [IV]
8±3[IV]
5±2[IV]
10 ± 0 [[V]
7± 1 [IV]
6±2 [IV]
No
No
No
Yes
Yes
Yes
55.8±84.5
160.3±73.7
135.5 ±55.6
105.0 ± 15.1
101.8 ± 40.3
203.4 ± 107.3
Phenytoin excreted as HPPH (%)Leff et al.[9J 6
8Borofsky et al.[37J 15
F3
12Leppick et al.[12J 7b
7"
25±22d
16±7d
10±5y
1-6y
7-20y
10 ±3y
10 ±3y
8±4[IV]
8±5[PO]
6±3[PO]
6±1 [PO]
5± 1 [PO]
7±3 [PO]
7± 3 [PO]
PB
PB
Yes
Yes
70"
49"
63.7 ± 20.2
58.3±30.0
64.5 ± 18.5
48.0±20.4
67.9±24.2
a Value taken from figure.
Abbreviations: d = day(s); IV = intravenous; PB = phenobarbital; PO = oral.
© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 29 (5) 1995
350
In children, the mean Km and mean Vmax valuesfor phenytoin range from 3 to 9 mg/L and from 5to 20 mg/kg/day respectively, with individual values ranging from 1 to 21 mg/L and from 4 to 25mg/kg/day (see table II).
As expected, the mean tY2z of phenytoin alsoshows a wide range in children (from 1 to 160hours), which at least partially depends on thedose/kg and initial concentrations at which they aremeasured (table II).
Effect of AgeChildren aged less than 5 years have more vari
able Km[29] and Vmax values than do older childrenand adults.[52]
Some authors have observed an age-related trendtowards increasing Km,[26,27] which has not beenconfirmed by others.[29-31] The effect of age onphenytoin V max is more marked, mean V max beingsignificantly higher in children than in adults andprogressively declining during childhood.[27,29-3l,52]This contrasts with data published by Grasela etal.,[65] who analysed previously reported phenytoinplasma concentrations from Japan,[29]England.U'Jand Germany (young adults)[59]and found Km butnot V max to be age dependent. However, this heldonly when a nonlinear function of bodyweight wasused to adjust for body size. In line with this assertion, after correcting for differences in the liverlbodyweight ratio in children and adults, Blain etaU 3l] found that V max is similar in the 2 groups. Itis therefore likely that the difference between children and adults in the phenytoin dose/kg requirement is due to the greater relative weight of theliver in children, and not to any qualitative or quantitative differences in the activities of the enzymeinvolved in the metabolism of phenytoin.
The more rapid elimination of phenytoin inchildren than in adults is confirmed by a positivecorrelation between the plasma concentration :dose/kg ratio (CID) and age during childhood, reported by many researchers.[3,4,8,37,45,55,66-70] On
the other hand, in neonates, the phenytoin elimination rate is particularly low, increasing during thefirst postnatal month; this accounts for the widerange of plasma concentrations observed when a
© Adis Internationai Limited. All rights reserved.
Battinoet al.
standard loading dose of phenytoin is administered,!6,23]
The most variable and longer ty2z values forphenytoin are observed during the first postnatalweek, when there is an inverse relationship between l'/2Z and postnatal age.[7,23,71] Nonlinear regression analysis gives the best fit of the relationship between l'/2Z and age during the first 36 daysof lifeP3] This variation in ty2z during the neonatalperiod is the result of truly age-dependent changes,given that there is a 60% decrease in l'/2Z betweenthe first and the fourth postnatal weeks even whenvalues are controlled for initial plasma concentrations.F"
Consequently, phenytoin ty2z values measuredduring the first postnatal month, when steady-stateplasma concentrations may not be achieved [seePainter et al.,[6,34] (table 11)], must be interpretedwith caution.
According to Loughnan et al.,l7] (but in contrastto Bourgeois and Dodson.F'J) phenytoin ty2z valuesare longer in premature than in full term neonates;however, it must be noted that the premature infants studied by Bourgeois and Dodson were theonly babies in their population not treated withconcomitant phenobarbital.
Effect of Concomitant TreatmentCo-medication also affects phenytoin elimina
tion kinetics. Phenobarbital is associated with anincrease in Km and V max, [27] the effect on Km beingconsistent with competitive inhibition and the effect on V max implying induction of phenytoinmetabolising enzyme.F" Phenobarbital-phenytoininteractions are therefore unpredictable: if the addition of phenobarbital primarily leads to an increase in V max, the elimination of phenytoin wouldbe accelerated and its concentration reduced; ifphenobarbital increases Km, phenytoin elimination would be reduced and its concentration increased. In general, these opposing effects canceleach other out[27.54,72,73] or lead to a decrease inphenytoin plasma concentrations.t'vf
Dodson[27] studied 5 patients treated with andwithout carbamazepine. In 4, carbamazepine wasassociated with a reduction in Km; and in all 5, with
Clin. Pharmacokinet. 29 (5) 1995
Ant iepileptic Dru gs in Paediatric Patients (II)
a reduction in Vmax' Consequently, it can be expectedthat the addition of carbamazepine will lead to alowering in phenytoin plasma concentrations.U'V' l
Data concerning the effect of valproic acid onphenytoin plasma concentrations are somewhat controversial. Dodson (27)found that the administrationof valproic acid does not alter Vmax but lowers Kmby displacing phenytoin from serum proteins, thusreducing total phenytoin but not unbound concentrations.
Effect of Other FactorsTh e results of an analysis made by Grasela et
aJ.l65) on the data provided by 3 previous studiesdid not indicate any gender-related effect onphenytoin kinetics.
The analysis did show that the Km values observed in Japanese patients are approxim ately 30%lower than tho se of age -matched Caucasian s; however, it is not clear whether this difference represents a true racial (i.e. genetic) effect, or whetherit is due to other systematic differences bet weenthe study groups (such as diet, dru g exposure orother factors).
Febrile illness may also alter the elimination ofphenyto in by enhancing the biotransformation ofthe dru g. Leppick et aJ.l1 2] (table I) observed a 22to 69 % decrease in phenytoin plasma concentration s, which was maximal 6.6 days after the onsetof illness : during follo w-up, plasma concentrationsreverted to pre-illness values. The fact that thelevel of phenytoin free fraction did not change indicates that the decrease in plasma concentrationsis unlikely to be due to decreased plasma proteinbinding. A pos sible cause of the drop in phenytoinpla sma concentrations is induction of the hepaticoxidative enzyme system. This may be supportedby an increase in concentrations of phenytoin metabolites, although not to a significant level. (12)
1.5Therapeutic Implications ofPharmacokinetic Properties
In children of all ages, the relationship betweendo se/kg and pla sma concentrations of phenytoin isunpredictable, unless the Km and Vmax values areknown. Evidenc e for this can be seen in the excep-
© Adis Intematlonal Umned. All rights reserved.
351
tionally high variability of the pharmacokinetic parameters reported in tables I and II, even in patientsof the same age and/or undergoing the same concomitant treatment.
At the beginning of phenytoin therapy, it is often difficult to attain therapeutic plasma concentrations because of the high elimination rate of phenytoin at low plasma concentrations; however, beyonda given point (which may vary widely between individuals), even a small increase in dose/kg canlead to a large increase in phenytoin plasma con centrations.
In children, the complexity of drug management is increased by age-related changes in phenytoin eliminati on pharmacokinetics and the relatively high frequency of polytherapies and febr ileillness. Phenytoin dose/kg adju stment is thereforegenerally more difficult than that of other AEDs , andis even more diffi cult in a paediatric population.
Rearranged form s of the classical Michaeli sMenten equation can be fitted to steady -sta teplasma concentration do sage dat a. Many techniques have been advocated as aiding do sage adjustments based on single-point concentration. Anumber of these dosing methodsI29.58,6o.61 .63] havebeen tested in children p7-29.31 .63)
No differences between the Ludden et aJ.l60JandMullenl61J techniques ha ve been found in ch ildren;(31) those researchers who have applied mostof the published methods in paediatric populations[62-64] agree in recommending that of Bayesianfeedback. l'vl
Nevertheless, although the correlation betweenpredicted and observed steady-state plasma concentrations of phenytoin is highly significant (evenwhen methods based on only 2 steady-state plasmaconcentrations are used) , the degree of concordanceis poor. Therefore, when the phenytoin dose/kg isincreased , mon itoring of phenytoin plasma con centration s is necessary, particularly in youngerchildren .1 14,27.311
Other methods of dose/kg calculation ha ve beenproposed , including methods based on the urinaryHPPH/phenytoin ratio[2] or, for neonates, the de termination of in vitro protein binding ;!381 how-
Clin. Phormocokinet. 29 (5) 1995
352
ever, although reliable, these methods are not applicable in clinical practice.
A wide range of recommended dosages both foremergency and for long term treatment has beenproposed (see table I); however, the range is sowide that these recommendations are practicallymeaningless. Nevertheless, some general suggestions can be made.
First, dose/kg requirements for phenytoin decline with age of the patient. On the basis of theMichaelis-Menten pharmacokinetic parameterscalculated for 135 epileptic children, Bauer andBlouin[30j suggested that the mean daily dose/kgnecessary to achieve a steady-state phenytoinplasma concentration of 15 mg/L is 9.5 mg/kg forchildren aged 0.5 to 3 years, 7.5 mg/kg for childrenaged 4 to 6 years, 7.0 mg/kg for those aged 7 to 9years and 6 mg/kg for those aged 10 to 16 years.The youngest age group would thus require 62%more phenytoin (mg/kg/day) than the oldest.
Secondly, at lower initial concentrations ofphenytoin, a greater increase in dose/kg may berequired; progressively smaller dose/kg increments should be made as the phenytoin concentrations rise.
Particular caution is needed when establishinga maintenance dose/kg of phenytoin during theneonatal period, because of the rapid changes inand more variable elimination of phenytoin. In neonates, who have initially high phenytoin plasmaconcentrations and relatively long tyzz values, thecombined effect of age-related changes and thenonlinearity of phenytoin elimination kinetics maylead to dramatic changes in dosage requirementover time. This means that plasma concentrationsshould be measured frequently, and that a numberof dosage adjustments may be necessary during thefirst postnatal weeks.
The general rule that the number of phenytoindoses required depends on tyzz holds. However,since tyzz is concentration-dependent, serial controls are required. In general, young children rarelyneed to take phenytoin more than twice daily;once-daily treatment may lead to large fluctuationsin plasma concentrations.
© Adis Internationai Limited. All rights reserved.
Batiino et al.
Another important point is that, in children,changes in CID ratios may occur when patients areswitched to another brand or formulation of thedrug. Finally, it must be remembered that the monitoring of phenytoin plasma concentrations and theadjustment of phenytoin dose/kg during illnessmay be necessary, especially if there are changes inseizure control.
Inhibited absorption in children fed by means ofa nasogastric tube may be a risk factor for poorseizure control in paediatric patients receivingphenytoin; a better approach might be to use intravenous phenytoin preparations or other AEDs untilnormal feeding can be resumed.
2. Carbamazepine
Carbamazepine is widely used in the treatmentof partial and generalised seizures; its antiepilepticactivity is also due to its active metabolite carbamazepine 10, ll-epoxide (carbamazepine epoxide),which in tum is metabolised to the inactive compound trans-l 0, II-dihydroxy-lO, l l-dihydrocarbamazepine (carbamazepine diol).
2.1 Absorption and Bioavailability
Carbamazepine can be administered orally orrectally; however, no data concerning its rectal administration in children are available. Absorptiondata are summarised in table V.
After the administration of a single dose ofcarbamazepine tablets, Cmax is reached between 2and 12 hours later. Because of the lack of an injectable formulation, no precise data are available concerning the absolute bioavailability of the drug.
Keely et aL!77j (table V) reported better absorption in children aged 5 to 10 years than in youngerand in older children. Since individual data wereavailable, we analysed the influence of age on absorption in the population studied by Rey et al.,[74jand found a significant negative correlation betweentmax and age in children aged 1 to 8 years (fig. 1).
A higher dose/kg of carbamazepine is neededfor the treatment of malnourished, epileptic children: Cmax and bioavailability are significantly reduced in protein energy malnutrition (table V) be-
Clin. Pharmacokinet. 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II) 353
2.2 Distribution and Protein Binding
• y = 1.187x + 10.807r2 = 0.819; p= 0.0347
Fig. 1. Effect of age on the time to absorption of carbamazepine.Abbreviation: tmax =time to maximum plasma concentration.
974 5 6Age (years)
•3
Carbamazepine is distributed rapidly and quiteuniformly to all tissues and organs without anypreferential affinity. High concentrations havebeen measured in the cerebral cortex,[33,97] cerebellum, heart, liver, lung and kidney.I?"
The only data on the CSF/plasma ratios ofcarbamazepine and carbamazepine epoxide in children are those published by Pynnonen et aU98] in9 children. The mean carbamazepine and carbamazepine epoxide concentrations in CSF as recalculated by us were 39 and 68% of the respectiveplasma concentrations (Pynnonen et al. reportmean values of 33 and 41 %, respectively).
Approximately 68 to 83% of carbamazepine and58 to 68% of carbamazepine epoxide are bound toprotein; binding values extrapolated from meansaliva/plasma concentration ratios are slightlylower, being 55 to 75% for carbamazepine and57% for carbamazepine epoxide (table VI).
Both carbamazepine and carbamazepine epoxide unbound plasma and saliva concentrationscorrelate well with each other and with their respective total concentrations; the correlation index
led/slow release formulations: mean Cmaxand meanAUC are, respectively, 74 to 86% and 78 to 94%of those of the conventional formulation, with nonsignificant differences in Cmin (table V).
cause of malabsorption and a possibly more rapidelimination.Fv'
A variety of different carbamazepine formulations are now available in most countries (syrup,plain tablets, chewable tablets and a slow releaseformulation), all of which differ in their rate ofabsorption and/or bioavailability (table V). Incomparison with tablets, syrup preparations have ashorter tmax.[84,91.92] The mean Cmaxand mean AUC
values of the chewable preparation are similar tothose of plain tablets,[90,93] although individual differences are reported; in one case of malabsorption(the carbamazepine tablet was recovered in thestool), absorption improved with the chewable formulation.P'J The only available paediatric studycomparing the absorption parameters of generic versus proprietary tablets failed to show any significant difference, in spite of the higher dissolutionrate of the former (see Hartley et al.;[83] table V).
At steady-state, there is a large interdose diurnalvariation in carbamazepine plasma concentrations(table V) and, to a lesser extent, in the plasma concentrations of carbamazepine epoxide and carbamazepine dioU95,96] The mean Cmax values of the 3compounds are significantly reduced at night; thefact that carbamazepine and its metabolites are allsimilarly affected suggests slower absorption(probably due to reduced gut motility) rather thanan increase in carbamazepine elimination.I'<'
Interdose variations in carbamazepine plasmaconcentrations may be reduced with more frequentdoses during the day;[82] however, the problem ofdividing doses over the night period still remains,and the risk ofpoor compliance is higher if the dosefrequency is increased. These problems can beavoided by using controlled/slow release preparations: with twice-daily administration, the meanfluctuation index [(Cmax - Cmin)/Cmean] is reducedby 35 to 42% (table V), and the reduction in diurnalfluctuations is higher than the 25% reported foradults.l85] The concentration profile of carbamazepine epoxide does not show any significant differences between the 2 formulations with respect tothe fluctuation index,[85] but absorption and bioavailability are slightly reduced with the control-
© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 29 (5) 1995
@ TableV. Carbamazep ine pharmacokinetic parameters in paed iatr ic patients I ~»a.". Reference No. of Age group Associated Dose tmax Cmax Cmm AUC Fluctuation V/F h?z CUF5' pts (y) therapy (mglkg) (h) (mgIL) (mgIL) (mglL' h) index (L/kg) (h) (Uh/k g)m3
Single dose0g Ray et al.[74] 7 N Yes 14 ± 7 4.3 ± 1.4 7.9 ± 1.2 1.5 ± 0.5 8.5 ± 2.8 0.133 ± 0.051::JQ. MacKintosh et 6 N Yes 5 ± 0 6.7 ± 3.5 4.2 ± 0.9 10.9 ± 5.2c3 al.[75]
~ Ray et a1.174] 5 5.1 ±2.6 Yes 19 ± 4 4.8 ± 3.3 7.5 ± 2.7 1.9 ± 0.8 9.2 ± 5.5 0.227 ± 0.173a.
~ Bano et al.(76) 6 11.3 ±3.0 10 ± 0 9.5 ± 0.9 9.2 ± 1.0 219.0 ± 40.0·
<6' 6" 9.4 ± 2.3 11 ± 1 10.5 ±0.9 3.5 ± 0.5 72.0 ± 1.0::J'or Keely et a1.177]b 19c 2.0-4.0 No 10 3.0 18.1(j)lP 5.0-9.0 No 10 2.7 15.3:< 10.0-15.0 No 10 4.7 26.3(I)a.
Moreland et al.[7BIb 6 9.1 ± 1.8 No 7 ±1 9.1 ± 3.1· 3.7 ±1 .8· 4.7 ± 0.8 23.6 ± 5.3 0.142 ± 0.028(saliva)
Bertilsson et al.1791b 3 11.3± 1.5 No 2 ±0 1.2 ± 0.1 30.7 ± 3.2 0.028 ± 0.003
Pynnonen et aI.IBO] 2 3.3 ± 2.4 10 ± 1 1.5 ±0.6 17.0 ± 2.2 0.062 ± 0.032
Steady -state
Conventional tabletsKeely et al.ln 1b 19c 2.0-4.0 No 10 5.0 3.1
5.D-9.0 No 10 4.3 4.8
10.0-15.0 No 10 6.4 8.0
Moreland et a1.17B]b 6 9.1 ± 1.8 No 15 ±2 bid 7.4 ± 1.7· 2.7 ±1 .0· 4.7 ± 1.7 8.0 ± 2.3 0.402 ± 0.079(saliva)
Bertilsson et al.[79lc 3 11.3 ± 1.5 No 6 ± 1 bid 1.2 ± 0.4 15.2 ± 5.2 0.056 ± 0.009
Pynnonen et aLISO) 9 7.4 ± 6.6 No/yes 10 ±4 20.8 ± 6.4
Rane et al.1811 2 11.5 ±2.1 16.3
Rylance et a1.162] 2 9.5 ± 4.9 No/yes 22 ± 7 od 5.0 ± 1.4· 4.1 ± 0.5· 0.9 ± 00· 173 ± 18 6.0±0.2 10.0 ± 3.8(saliva) 2 9.5 ± 4.9 No/yes 22 ±7bid 3.5 ± 2.1· 2.7 ± 0.1· 1.2 ± 00· 74
Hartley et al.I83)1> 12 10.6 ±2.8 No 20 bid 3.6 ± 0.5 10.2 ± 1.8 98.9 ± 17.0
Paxton et al[84] 8 10.8 ± 2.5 No 14 ±2bid 2.6 ± 0.5 55 ±20(saliva)
Eag'Olofsson at 21 7.5±2.6 No 19 ± 7 bid 9.4 ± 2.4 5.1 ± 1.4 180.0 ± 38.5 BO± 16Q al.l85]b~-
Battino et al.l86]b No/yes bid,tid"U 20 6.0-21.0 11.9 ±2.8 8.2 ±2.3 103.5 ± 23.9::J'
Pieters et al.)87].0 16 12.6 ± 2.9 No/yes 13 ± 4 bid, tid 8.8±2.8 5.5 ± 2.0 86.9 ±26.0 48 ±25:30 Ryan at al.(88
)d 18 4.0-16.0 No/yes 17 ±2bid 10.0 ± 16.0b 5.9 ± 1.200 Thakker at al.lB9]b 12 8.0-17.0 No/yes 233 ± 115 qidd 209.4'"S'
Comaggia et al.19O)I> 15 ~~ 6.0-14.0 No/yes 23 ±8 bid,lid 10.1 ±2.5 7.2 ± 2.1 52.7± 12.1to
Carbamazepine slow/controlled release S'-0
§ Eeg-Olofsson et 21 7.5 ± 2.6 No 19±7bid 6.9 ± 2.4 4.7 ± 1.4 NS 140.0 ± 38.5· · · 39± 16··· c
:0 a1.1B5]b ~
-0 12-'"
Antiepileptic Drugs in Paediatric Patients (II) 355
"'" '" for all these relationships are between 0.82 andE '" E<J) Cl '" 0.99.[41,99,101,104-108]'" C <J)- '"0.£ ~ The variability of carbamazepine protein bind-E C ~::J ::J 0
:~ ~ ~ ing depends on a number of factors, such as drugE::) Cl serum protein interactions, age, concomitant treat-"C~~ ~.~ ments and times of sampling.E" -
°cn:§A significant negative correlation between theg.§ ~
~;;o free fractions of both carbamazepine and carbam-E II ci~ ;g v azepine epoxide and serum a-acid glycoproteinc . ~ a.0", • (AAG) was found by Contin et al.,[109] who con-O~ ...
~~~ eluded that, within the range occurring clinically,en.I::. .-. (/) -[52 there is a proportionate increase in the binding ofzm E 'iii ~
+1 +1 ::J C C carbamazepine and its metabolite as AAG concen-co -e- E ·E IIN '" 'x ~ ~ trations increase.(/) (/) (/) Em .5. z z Z II .~ € Furthermore, in both in vivo and in vitro studies,... M ... ~ ~ ;:
'" 0 C\i .,; E '" ~ AAG concentrations have been found to be higherN N . N o~g+1 +1 '" +1 +1 Q) N >. in epileptic than in nonepileptic children, suggest-~ ~ <0 M ... o S' "'0
Oi co ;£ '" ,..: ~;~ll) m'" E '"
ing that the increase in serum AAG may be due(/) (/) (/) ~~~z z z to the enzyme-inducing activity of carbamaze-... ~ "< ": II; C/}
C\i u, E ~ pine.[109,1I0]+1 +1 +1 +1 :::J .. ~
N co a OliO,*"Recently, Kodama et al.l 11O] studied the in vivo<Xi .,; ,..: ,..: ~ ~ ~.!!!
(/) ~ ~~:a binding characteristics of carbamazepine andz (/) "?-c(/);.. (/) t-, z .~~.~ ~ carbamazepine epoxide in the sera of 23 childrenC\i "l ": z C\i M
.!~~~+1 +1 cltreated with carbamazepine alone. They found thatN +1 +1 +1 ... +1 ~.§ it-o so a "< 0 m
,..: m m :Bq-LO£ the affinity of carbamazepine for specific bindingill " ~.~
(/) c::>10~ sites was approximately 4 times greater than thatz :::JCTV.E.... 0'- 0.-
0 ~ ~ .... _:g- of carbamazepine epoxide. These results are con-+1 ~:;::;§Ci.l sistent with the 1.5- to 2.5-times lower carbamaz-.,; § ~5 Q)
%~ II :g ~ epine than carbamazepine epoxide free fraction
:i5 Ess ~and saliva/plasma ratios (table VI)." " ll) " o Q) • ~"C ;s
:i5 :i5 ;:: :i5 ::) s~o <5... N +1 ... co :>1 8 ~ ~ ~ Conflicting results have been reported concem-+1 +1 M +1 +1 D <tI ~ ::J eo ;! ;£ M
~M a E c (5 0) ing the relationship between age and both carbam-::) N N N C/) 0 > c:
~ II c"i azepine[IOO,1I0] and carbamazepine epoxide[99,IOO,102]0.-0 ttl .Q
<J) <J) <J) <J) <J) :5 Z ~:§ binding. The mean percentages of unbound carba-'" '" '" '" '" Q> ~ g- ~<:- ~ ~ ~ ~0 0 0 -g ~ II 0 mazepine in 20 neonates, measured in vitro in thez z z z z z Z ::Jcu..oCl- •
cord serum collected at the time of birth, were re-l!! «s.- > am ~ ~
e ~ en v
~ C\i a a m a c: N<tI g ~ f<a. spectively 31 and 30% for carbamazepine 12 mg/L
N +1 <0 ,..: 0 '" ·9 +1 C c II II ~:
'" 6 6 +1 6 ~ <q '" Cl <..> (/) - ._ and 4 mg/L, and 52 and 47% for carbamazepine6 C\i '">
'~~zmi<0 '" <Xi ,..: <0 a a ·0- <J) - ~iti8f-§~ epoxide 3 mg/L and 1 mglL;[III] in both cases the:6 !!!.l!! !!i ~ . ~~1U~~.0 -c compound values obtained are slightly higher thana ~ so ~ §-M ~~
.9C\1 ~.g~ ~ ~ [g~~N .c:_
*''" -s ~U)E .§>·et/)c8~ those reported in table VI for older children.-t~ ·lE -c-::J -O"'OII.I::.Q.
i ~ i .h "'-. ~~ ~.~~ 5§~z·§.5 According to most published studies,[99,IOO,103,104]-s ca~ i. a;
~7d arQ5 ~~. .~"[.g ~~ c:~ ~ §r-€a;0;
.0 a; 5 c:o~~~~~"8~ carbamazepine protein binding is not influenced0; 0; a;
'" 0;~ .~ -sa;
~ ~ ~ E'~ ~ '~E'~g0 Ii! 0; Q; ~§.,E Cl .g >- by concomitant treatments, although a slight de-x '" ClC J!! C x
~x~ -e ~ ~~ ::::;3:0.Eoa.1i~E~.:8'" '"'" '" >..c
~8 ra.c 0"0 Q)_~8,g~ in carbamazepine epoxide binding<D a: a:: ..... (,)~!f!., Ql~ crease was
© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 29 (5) 1995
356 Battino et al.
Table VI. Carbamazepine (C) and carbamazepine epoxide (C-E) free fraction and saliva plasma concentrations in paediatric patients
Reference Analysis Ultrafiltration Stimulation lime of No. of Age group Associated Free fraction orsampling patients (y) therapy saliva/plasma ratio (%)
(h postdose) C C-E
Free fractionMacKichan etal.[99]
Agbato et al.l'OO]
Tomlin et al.[101)
Riva et al.l102]
Riva et al.l103]
HPLC 37°C
HPLC 25± 1°C
HPLC FPI
HPLC FPI
HPLC FPI
HPLC FPI
HPLC 25°C
HPLC 25°C
HPLC 25°C
HPLC 25°C
HPLC 25°C
1-5
7±3
Fasting
3
6
8
Fasting
Fasting
fasting
3
3
24
68
14
14
14
14
10
10
11
22
17
5-20
1-20
3-17
3-17
3-17
3-17
<1
3-5
7-11
3-10
3-10
No/yes 24±4
No/yes 19±3
No/yes 32± 10
No/yes 25±3'"
No/yes 24±3'"
No/yes 23 ± 3**'
No 20±0
No 20± 1
No 23± 1 NSb
No 17±2 NS
PB 18±2
32±7
38± 1
37± 1
41 ±2
42 ± 1*b
34 ±5*
39 ± 11
Saliva/plasma ratioMacKichan et HPLC Yesal.I99]
Goldsmith & GLC YesOuvrierl41]
EMI~ YesBartels et al.[1041 EMI~ Yes
EMI~ Yes
EMI~ No
EMI~ No
Eeg-Olofsson et HPLC Yesal.[851
HPLC Yes
HPLC Yes
HPLC Yes
1-5
Peak
Lowest
Peake
Lowest"
24
91
51
17
15
17
15
21
21
21
21
5-20
0.5-18
0.5-18
4-13
4-13
4-13
4-13
No/yes
No
Yes
No
Yes
No
No
No
No
27±4
26±5
25±6
42±5
41 ±8
45±5
45 ± 11
27
26
27
24
43± 13
64
68
60
63
a Versus fasting samples.
b Versus youngest children.
c Slow-release formulation.
Abbreviations and symbols: EMI~ = commercially available enzyme multiplied immunoassay kit; FPI = fluorescence polarisationimmunoassay; GLC = gas-liquid chromatography; HPLC = high performance liquid chromatography; NS = not significant; PB =phenobarbital; * p < 0.05 vs following row, unless otherwise specified; ** p < 0.01 vs following row, unless otherwise specified.
found in 17 children co-treated with phenobarbitalin comparison with 22 children on monotherapy.D°3JAn increase in carbamazepine free fractionwas reported in 2 patients exposed to trimethoprimlsulfamethoxazole (from 16 and 17% to 27and 25%, respectively); after the withdrawal of thedrug, the free fractions returned to their originalbaseline values)1l2]
The time of sampling after the last dose may alsoexplain differences in the results (table VI): predose sampling values of carbamazepine free fractions have been found to be significantly higher
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than those determined in samples collected 3, 6 and8 hours after the morning dose.[lOI] However, theseresults were not confirmed by Eeg-Olofsson.Ufwho found no differences between mean peak andmean morning fasting saliva/plasma ratios with either the conventional or the slow release formulations of carbamazepine.
The saliva concentrations measured by meansof gas-liquid chromatography and enzyme multiplied immunoassay (EMIT®) are similar.U!' Stimulation of saliva flow by chewing gum significantly alters carbamazepine concentrations but not
cs-,Pharmacokinet. 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
to a clinically relevant degree, the mean differencebetween stimulated and non stimulated saliva/plasma ratio being in the range 1 to 5% (tableVI)P04]
The higher free fraction-related mean salivaconcentrations of carbamazepine and carbamazepine epoxide found by MacKichan et al.[99] (tableVI) may have been due to one or more of severalfactors: contamination of the saliva by unabsorbeddrug; the presence of carbamazepine binding protein in the saliva; evaporation of saliva during thecollection procedure; or the temperature of theultrafiltration (performed in most of the studies at25°C rather than at body temperature).
The carbamazepine VIFcalculated from plasmaconcentrations is about 1.2 L/kg (table V); thisvalue is consistent with those from saliva (4.7 to6.0 L/kg) [table V], the saliva levels being 25 to45% of those of plasma (table VI). This calculationhas been made assuming 100% bioavailability, andtherefore tends to overestimate VIF. VIF does notchange under steady-state conditions (table V).
The possibility of age-dependent changes incarbamazepine VIF is a controversial point: someauthors[74.801 have reported V/F values calculatedfrom plasma concentrations which are higher inchildren than those reported in adults. However,Moreland et al. [78] reported carbamazepine VIFvalues calculated from saliva concentrations whichare similar in children to those reported in adults.
2.3 Metabolism
Carbamazepine is almost completely metabolised, the most important pathway being the formation of carbamazepine epoxide; this primarymetabolite is almost completely converted tocarbamazepine diol.
Carbamazepine epoxide is found in plasma andsaliva at concentrations of, respectively, 12 to 59%and 34 to 41 % of the parent drug (table VII);plasma carbamazepine diol concentrations are, respectively, 53 and 250% of carbamazepine andcarbamazepine epoxide concentrations.l'vl Thisvariability may depend on the effects of age andconcomitant treatments. The correlation between
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357
carbamazepine epoxide and carbamazepine totalconcentrations is statistically significant in somestudies,[81,105,113] but not in others. [95, 107]
During long term treatment, the plasma concentration profiles of carbamazepine and carbamazepineepoxide are virtually synchronous, their postdoseconcentrations peaking at approximately 3 to 5 and4 to 6 hours, respectively.l82,96]
Higher carbamazepine epoxide/carbamazepine(table VII) and carbamazepine diol/carbamazepineratiosf951are reported in children receiving polytherapy, the most liver enzyme-inducing drugsseeming to be phenytoin, primidone and phenobarbital. On the contrary, the epoxidation of carbamazepine does not seem to be affected by ethosuximide, benzodiazepine or acetazolamide (table VII).In addition, carbamazepine epoxide/carbamazepineratios are increased by valproic acid, owing to inhibition of epoxide hydrolase. The effect of valproicacid seems to be greater in children already beingtreated with valproic acid who receive carbamazepine for the first time, than in those already treatedwith carbamazepine who receive valproic acid (table VII). Data from Rambeck et aLll181 (table VII)indicate that, in children being treated with valproicacid who receive carbamazepine for the first time,the carbamazepine epoxide/carbamazepine ratio ishigher during the first days of treatment than aftera few weeks. According to the authors, this mayindicate autoinduction of the metabolite.UV' alternatively, the effect might be due to autoinductionof another metabolic pathway not involving carbamazepine epoxide.
From the data of Rambeck et al.,' 118] we analysed the relationship between the valproic aciddose/kg and the carbamazepine epoxide/carbamazepine ratio, at the beginning of carbamazepinetreatment (from days 6 to 13) and at steady-state(after more than 30 days). The carbamazepineepoxide/carbamazepine ratio increased linearly inrelation to the valproic acid dose/kg during the initial phase (between days 6 and 13), but not atsteady-state (after more than 30 days). This suggests that patients treated with a relatively highervalproic acid dose/kg are more exposed to the risk
Clln. Phormacokinet. 29 (5) 1995
@ Table VII. Carb amazep ine epo xide and carbamazepine diol plasma concentrat ions in paedi at ric pat ients I ~»Q.,"' Reference Time of No. of Age Dose Plasma concentration (mglL) Plasma concentration ratio
~ sampling pts (y) (mglkg) carbamazepi ne carbamazepine carbamaze pine epoxidel carbamazepi nediol! carbamazepine diol!3 (h) epoxide carbamazelline carbamazepine ._ carbamazepine epoxides0 Monotherapy:JQ. Total p lasma concentrationsc:
Altafullah et al.1113J 5.6 ± 0.2 pd 101 551 ± 15" 1.5 ± 0.1 20± 63 11.0 ± 0.5 7.9 ±0.1ft Elyas et at,{l05J 7.2 ± 3 pd 30 11.8 ± 45b 17.2b 17± 1Q.
~ Furtanut et a1.111 4) 12.0 pd 45 7.8 ±3.6 18.9 ± 4.9 5.9 ± 1.9 1.7 ± 0.8
cB' Kumps & Mardensl11 5J 12 9.0 ± 3.0 15.1 ± 4.9 6.5 ± 2.5 1.5 ± 0.8 23 ±8~ MacKichan et al.199J 1.0-5.0 pd 4 5.0-20' 24 ± 7
*Pynnonen & Y~anaI116) 12.0 pd 10 7.3 ± 5.7 13.1±5A 5.3 ± 2.0 1.2 ± 0.7 24 ± 13
::: Pynnonen et al.1981 6.0 ± 2.0 pd 27 7.2 ± 5.2 12.5 ± 4.6 5.2 ± 1.2 1.2 ± 0.7 24 ± 12(J)Q.
Rane et al.181J 1.8-15b12.0 pd 23 1204± 4.3 504± 2.1 0.7 ± 004 12 ± 5
Riva et al.(102) 12.0 pd 10 0.8 ±0.1 20.9 ± 0.7 4.3 ± 0.5 1.3 ± 0.2 29 ±7
12.0 pd 10 3.6 ± 0.6 21.9± 1.0 5.8 ±0.8 NS 1.7 ± 0.3 NS 30 ±6 NS
12.0 pd 11 8.5 ± 0.5 19.8 ± 0.8 6.1 ± OA' 1.3 ± 0.1 NS 22 ± 4"Riva et al,{l03) 3.0 pd 22 6.0±2.1 1804 ± 7.2 7.0 ±2.1 1.3 ± 0.5 18 ± 8
Schoeman et al.lm l Variable 25 2.0-19" 16.0 8.3 ± 2.2 2.3 ± 1.2 19± 8
Hartley et al.1981 1200h 20 11.1± 24' 15.2 ± 38' 6.0± 1.3 1.3 ± 004 21 ± 4 53 ± 13 250 ± 53
4.0 pd 19 11.1 ± 24' 15.2 ± 38' 9.7 ± as" 1.7 ± o.s" 17 ± 3t tt 34 ± 7 199 ± 34
2400h 20 11.1 ±24' 15.2 ± 38' 5.8 ± 104 104± OAtt 20 ± 4 50 ± 14 250 ± 58Free plasma concentrations
Elyas et a1.1105) 7.2 ± 3 pd 30 11.8 ± 45b 17.2" 35 ± 2Riva et al.{l02J 12.0 pd 10 0.8± 0.1 20.9 ± 0.7 0.9 ±0.1 0.5 ± 0.1 56 ± 14
12.0 pd 10 3.6 ± 0.6 21.9 ± 1.0 1.2 ±0.1 0.7 ±0.1 59 ± 12
12.0 pd 11 8.5 ± 0.5 19.8 ± 0.8 1A ±0.1' 0.6 ± 0.1 41 ± 12"
Riva et al[ 1031 3.0 pd 22 6.0 ±2.1 1804± 7.2 1.2 ± 004 004± 0.2 34±8
Rylance et al.{l07J Hourly 6 7.3 ± 4.7 17.7 ± 5.5 41 ±24t
Paxton et al.'841 Hourly 11 6.0-15.0 13.5 ± 2.9 7.6 ± 2.5 2.7 ± 0.9 34 ±9
PolytherapyTotal plasma concentrations
Q Furlanut et al.ll14J 12.0 pd 37 804± 4.9 2204± 6.7 4.6 ± 1.8 1.6 ± 0.8'?" Kumps & Mardensl11 5j 9 1104± 4.3 13.8 ± 4.3 604± 3.0 1.5 ± 0.8 23 ± 7 NS'U
MacKichan et al.1991 1.0-5.0 pd 5.0-20· 45 ± 2' "::r 200
:3 Pynnonen et al.l981 variable 10 9.6 ± 4.2 16.9 ± 6.0 5.1 ± 1.7 1.6 ± 0.8 30 ±13NS0
Rane et al[ 81J 1.8-15b0 12.0 pd 20 14.3 ± 5.6 3.7±2.1" 0.8 ±0.5 NS 24 ± 15'0z;:J Phenobarb ital
~~ Total plasma concentrationsIV-0 Riva et al.ll03J 3.0 pd 17 6.0 ± 2.7 21.8 ±8.1 5.9 ± 1A' 1.3 ± 0.1 22 ± 4" S·2J 0
:0 Schoeman et al.lm l variable 2 2.0-19b 16 9.9 ± 1.7 NS 1.6 ± 1.3 NS 15± 11 NS ~-0 f2..'"
@ Free plasma concentrations ;J>» :::Co Riva et alP 031 3,0 pd 17 6 ,0 ± 2,7 21,8 ± 8,1 1,0 ±0,2" 0,5 ± 0,1 48 ± 12' " -,"' /ii'
~ Phenytoin "8.in
5 Total plasma concentrations ~5- Allalullah et al.(1 131 5.7 ± 0.7 pd 11 12.7±2.2 913± 105" 7.6 ± 0.9 2.3 ±0.3' 33 ± 3'" n':> 0Q. Elyas et al.(1051 7,2 ±3pd 9 11.8 ± 45b 17,2b 25 ±2'" ..,~
cPynnonen & Yrjiln ii l116) 12,0 pd 3 10,7 ± 2.4 8,0± 1,5 4,9 ± 3,0 NS 1.1 ±0,6 NS 25 ± 7 NS oe
'"Vl
s Schoeman et al.l1171 Variable 6 2,0-19b 20 23 ±3 NS 5'
~ Free plasma concent rations "0""6' Elyas et al[105] 11.8±45b 17,2b I'tl
7,2 ± 3 pd 9 45±5' 0..zr s;;;
Prlmldone q
~ Total plasma concentrations n'"0:<
Altafullah et al.l11 3] 5,0 ± 0,7 pd 10 10,3 ± 2,2 926 ± 83' 7.7 ± 0,5 2,1 ± 0,2" 28±2'" ""<1> 0',P- I'tlValprolc acid :::Total plasma concentrations
(jj-Alla fullah et al.l1131 5,5 ± 0.7 pd 13 12,8 ± 1.4 617 ± 64" 7.5 ±0.5 2.6 ± 0.3" 36±5'" -Rambeck et al.l1181 c 14 13.5 ± 4,6 4,6 ±2,0 5.3 ± 4.0 116± 76
14 8,6 ± 6,2 35.5 ± 11,8 6,9 ± 2.4 4,7 ± 1.2 73 ± 30
Elyas et a1.1105\ 7,2 ± 3 pd 12 11,8 ± 4,Sb 17,2b 24 ± 5'"
Schoeman et al.l117] Variable 27 2,0- 19b 18 7,7 ± 2,7 NS 2.3 ± 0.8" 30 ± 13 NS
MacKichan et al.l991~1 , SS pd 10 S,0-20' 41 ± 11'"
Free plasma concentrations
Elyas et al[1051 7,2 ±3pd 12 11.8 ± 4,Sb 17,2b 46 ± S'
AcetazolamideTotal plasma concentrations
Schoema n et al.l11 71 Variable 5 2.0-19b 21 8,8 ± 1.0 NS 1.7 ± 0,7 NS 21 ± 11 NS
BenzodlazepinesTotal plasma concentrations
Elyas et al.11051 7,2 ± 3 pd 15 11,8 ±4,Sb 17,2b 20 ±2 NS
Pynnonen & Yrjilnii(1161 12.0 pd 3 6,8 ± 3.4 16.0 ± 4.7 5.4 ± 1.9 1.2 ± 0,5 24 ± 7 NS
Schoeman et al.l1171 Variable 5 2,0-19b 17,0 6,3 ±2,1 NS 0,9 ± 0,6 NS 12 ± 5 NS
Free plasma concentrations
Q Elyas et al [' 051 7,2±3pd 15 11,8 ± 4.5b 17.2b 40 ± 3 NS~r
Ethosuximide~0 Total plasma concentrations
~ Altalullah et al.l1131 S.4 ± 0,6 pd 20 11,9 + 1,2 668 ± 36' 7,5 ± 0.4 1,6 ± 0,1 NS 22 ± 1 NSo
In mg/m2,0 a
'"5' b No differentiation between monotherapy and polytherapy,~ c Plasma samples taken 1 to 6 days alte r the start 01carbamazepine therapy in patients receiving valproic acid ,~ d Plasma samples taken >30 days after the start 01.carbamazepine therapy in patients receiving valproic acid ,~ Abbreviations and symbols: NS = not significa nt; pd = postdose ; pts = patients; , p < 0.05 vs monotherapy; " p < 0,01 vs monotherapy ; . " p < 0,0 01 vs monotherapy; • p < 0,05 vs younger
~ children ; • p < 0.01 vsyounger children and 3- to 5-year-old children; t no difference found at any time during the 12-hou r interval; It p < 0,01 vslasting samples; ttl p < 0.001 vs fasting samples,I ~'"
360
of adverse effects owing to the high epoxide concentrations observable during the first days ofcarbamazepine treatment.
The effect of age on carbamazepine epoxidationis another controversial point: higher proportionsof carbamazepine epoxide in children than in adultshave been reported in most,l95,98, 102, 105, II 3-1 15,118,119]but not all,II03,ll7] studies. It is possible that thehigher carbamazepine epoxide/carbamazepine ratios found in younger children by Riva et al.[l02]were due to an age-related increase in the conversion of carbamazepine to carbamazepine epoxideand an age-independent degradation of carbamazepine epoxide. In contrast, in 8 children lowercarbamazepine diol/carbamazepine ratios werefound in comparison with adults, probably due tothe greater renal clearance of carbamazepine diol(see below).195]
2.4 Elimination
Urinary excretion in children of carbamazepineepoxide and carbamazepine diol is, respectively, 2and 36% of the carbamazepine dose; similar valuesare found in adults,!95]
In children, the renal clearance of carbamazepine epoxide and carbamazepine diol is, respectively, 0.0096 L/h/kg and 0.0828 L/h/kg,195] theclearance of carbamazepine epoxide being similarto that found in adults and that of carbamazepinediol being significantly higher; this may explainthe lower carbamazepine diol : carbamazepine ratio observed in children.P>'
Carbamazepine t'/2Z varies from 2 to 36 hours(table V). Time-dependent changes in eliminationkinetics are well established, and are documentedby the results of the 3 within-patient studies withsingle and multiple dose determinations listed intable V. They occur at a very early stage of treatment: Bertilsson et a1.179] reported that the meanclearance of radiolabelled carbamazepine administered on the second day of treatment was 34%higher than after the first dose; clearance doubledafter 17 and 32 days of treatment, but no furtherincrease was noted during the next 4 months.
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Battinoet al.
Age-dependent changes in carbamazepine elimination kinetics are also well documented: theelimination ofcarbamazepine in children is considerably faster than that reported in adults;174,78,80,82]furthermore, the data concerning the influence ofage on carbamazepine CID ratios in both betweenpatientI52,95,103,113-115,120-124] and within-patient! 125]
studies consistently show an increase in C/D ratioswith age that is particularly evident in children onmonotherapy.
Nevertheless, autoinduction and age-dependentchanges in elimination kinetics cannot completelyexplain the great variability of tY2z, which is alsoevident in single dose studies.
Using the individual data of the first 4 studieslisted in table V,an attempt was made to understandthe differences observed in the 4 populations; theseresults are summarised in table VIII. Significant differences in mean t'/2Z ' relative clearances, dose/kgand ages were found between one study and another, a shorter tY2z and higher relative clearancesbeing associated with higher dose/kg and youngages. Furthermore, it is worth noting that shortertY2 and higher CL/F values were observed in the 5patients studied by Rey et al.;174] these patientswere the only ones concomitantly treated withother AEDs.
Changes in the carbamazepine C/D ratios suggest that changes in elimination are due to druginteractions: dose-related plasma concentrations ofcarbamazepine are lower in patients receivingpoly therapy, 18 1,103,120-122] particularly when carba-mazepine is given in combination with barbiturates I81,103,121] or more than 1AED.II13,121,123] On the
contrary, the administration of macrolides has beenreported to increase plasma carbamazepine concentrations by 75% within 2 or 3 days;lI12,126,127[erythromycin has in fact been successfully used asan inhibitor of carbamazepine metabolism to improve seizure management in compliant youngchildren with drug-resistant epilepsy.I'F'l
Many authors have reported a statistically significant negative correlation between the dose/kgof carbamazepine and its C/D ratio or, reciprocally,a positive correlation between the dose/kg and
Clin. Pharmacokinet. 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
Table VIII. Mean differences in carbamazepine pharmacokinetics in paediatric patients receiving a single dose
361
Studies compared
Rey et alF4J vs Bertilsson et al.[79)
Rey et al.[741 vs Moreland et al.[78J
Rey et al.[74J vs Pynnonen et al.[80]
Pynnonen et al.[80J vs Moreland et al.[78]
Bertilsson et al.[79] vs Moreland et al.[78J
Bertilsson et alF9J vs Pynnonen et al.l80]
h,z(h)
-21.53'
-14.38'"
-7.75'
--6.63 NS
7.15 NS
13.78 NS
CUF(Uh/kg)
0.19956'
0.16506 NS
--0.034 50 NS
Age(y)
--6.3'
-4.0'
1.8
-5.7
2.3
8.0
Daily dose(mg/kg)
16.64'
11.26'"
8.42"
2.85'
-5.38'
-8.22
Correlation (Kruskall-Wallis test) p < 0.006 P < 0.004 P < 0.01 P < 0.003
Abbreviations and symbols: CUF =clearance; NS =not significant; t,,;z =terminal elimination half-life; • p < 0.02 (Mann-Whitney test);.. p < 0.05 (Mann-Whitney test); ... p < 0.006 (Mann-Whitney test).
carbamazepine clearance or its dose/kg/level ratios,D21-123,128-131] even in subgroups which are ho-
mogeneous in terms of age and associated therapy.l121,123,131] On the basis of these findings, it has
been hypothesised that there is no linear relationship between carbamazepine plasma concentrationsand dose/kg)131] The hypothesis of a dose-dependent impairment of absorption has been ruled out byHartley et al.,[131] who pointed out that this wouldlead to dose-related changes in the plasma metabolite CID ratios: something which has not beenobserved. It is therefore more likely that the variability in disposition of carbamazepine depends ona combination of time, age and dose-dependentchanges in carbamazepine elimination kinetics.
Values of tl/2z of 26 hours for carbamazepine and16 hours for carbamazepine epoxide have been calculated in a 13-year-old girl receiving long termcarbamazepine therapy who accidentally ingestedan overdose of carbamazepine 34g and clonazepam80mg; these relatively prolonged tl/2z values havebeen attributed to an inhibitor interaction withclonazepam or, alternatively, to protracted absorption due to a marked decrease in intestinal motility)132] The latter hypothesis is consistent withthe finding of delayed absorption in 2 other girls(aged 18 months and 17 years) with overdose.l'V'in whom peak carbamazepine plasma concentrations occurred after 4 to 6 and 15 hours, respectively; the corresponding tl/2z values were 11 and17 hours.
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2.5 Therapeutic Implications ofPharmacokinetic Properties
Given the pharmacokinetic properties of carbamazepine, the correlation between daily oraldose/kg and steady-state concentrations is poor:some studies have failed to find any statisticallysignificant correlation;[95,105,114,128] others havefound only a weak correlation, mainly in patients oncarbamazepine monotherapy.[81,101,103,120,123,130,J31]
However, the correlation between carbamazepinedose/kg and the plasma concentrations of the 2 metabolites are highly significant.[95,105,113,J ]9,131]
Consequently, if seizures fail to be controlled or adverse effects occur, monitoring of plasma concentrations may be necessary.
Initial carbamazepine dose/kg should be considerably higher in younger children and in children receiving combination AED therapy. However,caution is needed when administering carbamazepine to patients already being treated with valproicacid, particularly when valproic acid is administered at a high dose/kg. The adverse effects due tohigh epoxide concentrations can be avoided byslowly increasing the carbamazepine dose/kg or byreducing the dose/kg of valproic acid. It may benecessary to determine the concentration of the epoxide when adverse effects occur in patients receiving valproic acid who subsequently receive additional carbamazepine therapy.
The administration of macrolides to patients receiving carbamazepine may lead to unexpectedand severe intoxication within 2 or 3 days: when-
Clin. Pharmacokinet. 29 (5) J995
362
ever possible, the use of these drugs must be avoidedand, when this is not possible, carbamazepineplasma concentrations should be closely monitored(preferably every day) . If necessary, the carbamazepine dose/kg must be adjusted during and afterantibiotic therapy, on the basis of plasma concentrations. Sulphonamides have also been reported toincrease the carbamazepine free fraction.
Slow-release preparations can be taken twicedaily. Infants receiving a suspension or a chewableformulation should be given frequent doses duringthe day, in order to limit interdose variations inplasma concentrations; an additional dose may benecessary during the night.
The routine monitoring of unbound plasma concentrations is not necessary, nor is the monitoringof carbamazepine epoxide plasma concentrations.In children, salivary monitoring may be used instead of plasma monitoring.
3. Sulthiame
Sulthiame is a sulphonamide derivative whichwas introduced about 30 years ago for the treatmentof epilepsy; today it is used rarely, and generally incombination with other AEOs .
May et al.[1 341have recently studied the pharmacokinetics of sulthiame in 31 children and 55 adultswhere the dose of sulthiame and any co-medicationhad not been changed for at least 5 days. In children,for doses of sulthiame between 3 and 25 mg/kg(mean ± SO: 11 ± 6 rug/kg), plasma concentrationsranged from 0.6 to 15.9 mg/L (4.4 ±3.6 mg/L). Therelationship between dose/kg and plasma concentrations of suthiame was statistically significant,and children had significantly lower plasma concentrations than adults receiving a comparabledose/kg,
Concomitant treatment with carbamazepine (butnot with valproic acid and phenobarbital) decreasessulthiame plasma concentrations.U P!
The sulthiame elimination tY2z was estimatedfrom plasma concentrations of 6 children and 5adults, after the withdrawal of sulthiame. The meantJ/2Zwas shorter in children than in adults (7 ± 2hours vs 12 ±2 hours), a result which is in line with
© Adi s Internotionollimited. All rights reserved.
Battino et al.
the greater daily fluctuations of plasma concentrations in children (140 ± 53% vs 59 ± 29%).[1 34)
May et al.f134) recommend starting sulthiame therapy at a dose of about 5 mg/kg, subsequently increasing it to 10 mg/kg over a period of 1 or 2 weeks;a higher dose/kg may be used if no adverse effectsoccur. Given the short tY2z of sulthiame, steadystate plasma concentrations are reached within afew days; for the same reason, the daily dosageshould be divided into 2 or 3 administrations.
4. New Antiepileptic Drugs
4.1 Lamotrigine
Lamotrigine is a new anticonvulsant used in thetreatment of both partial and generalised epilepsies. The only available data concerning lamotrigine pharmacokinetics in children has been presented in abstract form,l135,136j and are summarisedin table IX.
4. 1.1AbsorptionLamotrigine is rapidly absorbed by the gastro
intestinal tract ; after oral doses of about 2 mg/kg,Cmax values of 0.5 to 2.1 mglL are attained after 1to 6 hours in children aged 0.5 to 5.5 years .1135] Inpatients treated with liver enzyme-inducing AEOs ,steady-state plasma concentrations of lamotriginevaried from 0.1 to 7.3 mglL for oral doses of between2 and 18 rug/kg per day; in patients being treatedwith valproic acid, oral doses of between 1 and 9mglkg per day correspond to plasma lamotrigineconcentrations of between 0.1 and 12.1 mglL.[137.138]
4. 1.2 ElimlnafionThe mean ty2z of lamotrigine varies from 8 to 45
hours, the main reason for this variability beingconcomitant treatment: lamotrigine t'/2Z is significantly reduced by liver enzyme-inducing drug sand delayed by valproic acid (table IX) . The factthat lamotrigine CID ratios are higher in patientstreated with valproic acid than in patients treatedwith enyzme-inducing AEOs supports these results .[1 37.138]
Clin. Phormacokinet . 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II) 363
Table IX. Lamotrigine pharmacokinetic parameters in paediatric patients
Reference No. of Age group Dose Associated Samplingpatients (y) (mglkg) therapy period number
tmax
(hours)Cmax
(mg/L)AUG(mgIUh)
t1,.~z
(h)
44.7 ± 10.2"
~10.6 in 617patients
15-26.6 in 8/9patients
54-92
7.7±1.8
21.9 ±6.7
8.8 ±2.4
27.1 ± 10.1
43.7± 18.6"
0.8±0.2
1.2±0.6
1.4 ±OS
3.3 ± 1.4
4.9 ± 1.8
3.2±1.7'
VPA
EI+VPA
2
9
11 2.2±1.2 2.0±0.4a EI 48 6
10 2.5±1.4 0
10 3.0 ± 1.7 VPA
Wallace[136J 7 5-11a EI
VauzelleKervroedenet al.l135)
a All patients.
Abbreviations and symbols: AUG =area under the plasma concentration-time curve; Gmax =maximum plasma concentration; EI =enzymeinducers; 0 =others (i.e. drugs with no known interaction); tmax =time to Gmax; t,&Z =terminal elimination ha~-life; VPA =valproic acid; , p < 0.05(Kruskall-Wallis test); " p < 0.001 (Kruskall-Wallis test).
4.1.3 Relationship Between Dose/Kilogram andPlasma ConcentrationsPlasma lamotrigine concentrations increase sig
nificantly with dose/kg both in children treatedwith valproic acid and in children receiving monotherapy or treated with AEDs other than valproicacid;!137] however, lamotrigine plasma concentrations are more variable when children are treatedin combination with valproic acid;[137,J38] the widescattering of plasma lamotrigine concentrations ateach dose/kg was such that this relationship has nopredictive value.[l37,138j
4.2 Vigabatrin
y-Aminobutyric acid (GABA) is one of the major inhibitory transmitters in the central nervoussystem, and vigabatrin (y-vinyl-GABA) was initially synthesised as a result of a rational approachto isolating compounds which inhibit GABA transaminase (GABA-T), the enzyme responsible forGABA inactivation. Vigabatrin increases GABAconcentrations in CSF and is also effective in thetreatment of partial epilepsies and West syndrome.Vigabatrin is administered as a racemate, althoughonly the S(+)-enantiomer is active.[J39]
Rey et al.[l40,141] have investigated the pharmacokinetics of vigabatrin enantiomers after the oraladministration of a single racemic 50 mg/kg doseto 2 groups of 6 epileptic children (aged 5 monthsto 2 years, and 4 to 14 years, respectively). The
pharmacokinetic parameters for both age groupsare given in table X)140,141]
4.2. 1 Absorption and BioavailabilityVigabatrin is rapidly absorbed by the gastroin
testinal tract. Absorption is more rapid and morecomplete in older than in younger children; thisdifference is reflected in the bioavailability of thedrug, since the AVC is significantly greater inolder children.
In contrast to adults,' 139] in whom the tmax of theR(- )-enantiomer of vigabatrin is about twice thatof the active S(+)-enantiomer, no differences werefound in the tmax of the 2 allosteric forms in children. The mean Cmax of the R(-)-enantiomer always exceeded that of the active S(+)-enantiomer;the tmax was similar for both isomers. The meanAVC of the R(- )-enantiomer was also significantlygreater than that of the S(+)-enantiomer. The AVCvalues for each isomer are significantly lower ininfants than in children, which in tum are lowerthan in adults.
The mean R(- )/S(+)-enantiomer Cmax ratioswere 1.6 and 1.8 in children with epilepsy aged 5months to 2 years and 4 to 14 years, respectively)140,14l jThe plasma concentration of both enantiomers was similar at 6 and 24 hours after administration.
During the long term administration ofvigabatrin 50 mg/kg twice daily, mean morningfasting plasma concentrations varied from 2.0 to
© Adis International Limited. Ail rights reserved. Clin. Pharmacokinet. 29 (5) 1995
364 Battinoet al.
Table X. Vigabatrin pharmacokinetic parameters in 2 groups of 6 paediatric patients (grouped according to age)[141 .1421
Age group Dose AT tmax Cmax AUC V/F h2z CUF(mglkg) (h) (mglL) ' (mglL· h)' (Ukg) (h) (Uh /kg)
12.1 ±5.9mo 50 Yes S 2.85 ± 1.61 13.9 ± 4.5 90.9±27.9 4.63±1 .12 5.65 ± 1.52 0.591 ± 0.165
R 2.35 ± 1.87 NS 21.0 ±6.6' 106.0 ± 28.5' 2.01 ±0.68' 2.87 ± 1.03' 0.198 ± 0.110'
8.7 ± 3.8y 50 Yes S 1.36± 0.96 23.8 ± 12.2 117.0 ± 26.0 3.48 ± 1.23 5.47 ± 1.93 0.446 ± O.t 03
R 1.28 ± 0.58 NS 41.3 ± 13.9' 147.0 ± 34.0' 2.77 ± 1.19 5.68 ± 2.86 NS 0.355 ± 0.083"
Differences between S p < 0.05age groups R NS
NSP <0.05
p<0.05P <0.05
NSNS
NSP < 0.05
NSP <0.05
a Calculated for a dose of 50 mglkg .
Abbreviationsandsymbols:AT=associated therapy; AUC =area under the plasma concentration-time curve; CUF =clearance; Cm•x=maximumplasma concentration; mo =months; NS =not significant ; pts =patients; R= R(-) enantiomer; S =S(+) enantiomer; h,z =terminal eliminationhalf-life; tm• x =time to Cmax; V/F =apparant volume of distribution; " p < 0.05 vs previous row unless otherwise specified.
3.8 mg/L for the R(-)-enantiomer and from 1.5 to3.0 mg/L for the S(+)-enantiomer.
There is no accumulation of either of the vigabatrin enantiomers, evidence for this being that themean morning plasma concentrations of both donot significantly increase over a 4-day period. Theplasma concentrations of vigabatrin at 1 hourpostdo se also show no signs of an increase over 4days. One hour after dose admini stration, meanplasma concentrations varied from 10.3 to 17.4mg/L for the R(- )-enantiomer and from 16.0 to28.0 mg/L for the S(+)-enantiomer.
4.2.2 DistributionLarger V/F values were found for the active
S(+)-enantiomer only in younger children; no differences were observed between children with epilepsy aged 5 months to 2 years and those aged 4to 14 years.l140.141] Smaller VIF values have beenmeasured in adults.l 139]
4.2.3 EliminationIn children, the renal excretion of unchanged
drug is the main route of elimination; no metabolites of vigabatrin have been identified. Theamount of the drug excreted has been calculated in5 children, whose consecuti ve complete urine collections were pooled for the measurement of bothenantiomers. The 20- to 23-hour urinary recoveryof R(-) and S(+) isomers, respectively, varies from21 to 48% and from 20 to 37% of the dose ; the renalclearance calculated in these 5 patients was 0.059
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to 0.187 L/h/kg for the R(-) and 0.031 to 0.120L/h/kg for the S(+) enantiomers.
The mean t'l22of the S(+)-enantiomer is significantly longer than that of the R(-)-enantiomer, butonly in younger children.
The t'l22 and clearance (e L/F) values for the R(-)enantiomer are shorter and higher in younger children; the kinetic parameters of the S(+) enantiomerdo not vary with age.
4.2.4 Therapeutic Implications ofPharmacoklnetic PropertiesIn 16 children, the correlation between vigabatrin
dose/kg and plasma concentrations at steady-statewas found to be poor ;[1421in the 7 patients whosedrug dosage was increased twice during the study,there was a linear relationship between meandose/kg and mean plasma concentrations (althoughthere was considerable intra- and interindividualvariability and, in some patients, no dose-relatedincrease in plasma concentrations).
Arteaga et al.l1421 recommend starting vigabatrin treatment at a dose of 50 mg/kg, increasingto 75 mg/kg or even 100 mg/kg only when a partialclinical response is observed.
Rey et al.[14 IJconclude that the absence of anysignificant differences between children with epilepsy aged 5 months to 2 years and those aged 4 to14 years, in terms of the pharmacokinetic parameters of the biologically active S(+) enantiomer ofvigabatrin, does not support the use of a differentdose/kg according to age between 1 month and 15years old.
Clin. Phormocokinet . 29 (5) 1995
Antiepileptic Drugs in Paediatric Patients (II)
4.3 Oxcarbazepine
Oxcarbazepine is a keto-derivative of carbamazepine, and has a similar efficacy profile. In humans,oxcarbazepine is almost immediately completelymetabolised to the active compound lO-hydroxycarbazepine.
The only available data concerning oxcarbazepinepharmacokinetics in children are those presentedat the Annual Meeting of the American EpilepsySociety, in New Orleans in December 1994.[143] 31children aged 2.3 to 12.5 years received a single 5or 15 mg/kg dose of oxcarbazepine. Results wereexpressed as Cmax (umol/L) divided by the actualadministered dose/kg (Cmax/D ratio).
Oxcarbazepine Cmax/D ratios of 0.46 to 0.60were reached at about 1 hour postdose; they do notseem to be correlated either by age or by dose/kg.
10-Hydroxy-carbazepine Cmax/D ratios of 2.72to 4.48 were reached at 3 to 4 hours postdose. TheCmax/D ratio decreased significantly with increasing dose/kg but was not influenced by age. TheAVC values increased significantly with age(-40%). V/2Z increased significantly with dose/kg(45%) and age (58%).
The authors[143] conclude that the same initialdose/kg could be administered to children aged 6to 12.5 years and to adults; it should be higher in2- to 6-year-old children. The large interindividualvariability observed should lead to individual adjustment of this dose/kg for an appropriate therapeutic effect.
4.4 Felbamate
The results of a retrospective analysis of felbamate concentration data from paediatric and adultpatients in 6 studies were presented at the samemeeting as those on oxcarbazepine pharmacokineticsJl44] A total of 3345 evaluable plasma concentration values for felbamate were available from700 patients aged 2 to 74 years. The analyses useda nonlinear mixed-effect pharmacostatistical modelling technique (NONMEM). Factors in the modelincluded age, body weight and concomitant AEDs.Felbamate CL/F, as calculated by NONMEM, was
© Adis International Limited. All rights reserved.
365
higher in children younger than 13 years than inolder patients by about 40%. In addition, felbamateCLIF was found to be inversely correlated with agein a study of 30 patients with epilepsy aged 2 to 17years:[145] patients older than 10 years had a meanCL/F of 34 ml/h/kg, and younger patients had amean CL/F of 61 ml/h/kg.
Therefore, as for other AEDs, younger childrenrequire a higher dose/kg compared with adolescents and adults.
5. Conclusion
For the majority of patients with epilepsy, onsetoccurs during childhood, when the maturationalprocesses of the brain are still in evolution. Themanagement of infantile epilepsies should thus beaimed at reducing the risk of seizure-related effectson the physiological development of neurologicaland psychological functions.
Pharmacological treatment is an important partof this approach, and may significantly contributeto improving the prognosis of infantile epilepticsyndromes. In assessing a rational drug prescription in childhood, a number of age-related factorsmust be taken into account; the absorption, distribution, metabolism and elimination of differentantiepileptic drugs all change to different extentsduring postnatal life.
This review, together with Part I, is intended toprovide the reader with a summary of the most relevant information that must be known by physicians involved in the care of childhood epilepsy.
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Correspondence and reprints: Dr DinaBattino, Neurological Institute Carlo Besta, Via Celoria 11, 20133 Milan, Italy.
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