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Paediatric Antiretroviral PK David Back University of Liverpool, UK

Paediatric Antiretroviral PK David Back University of Liverpool, UK

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Page 1: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Paediatric Antiretroviral PK Paediatric Antiretroviral PK

David BackUniversity of Liverpool, UK

Page 2: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #2Pediatric Developmental Pharmacology

Page 3: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #3

PK in Paediatric Populations

Developmental changes can significantly affect ADME

Majority of PK data in paediatric patients obtained in older children

Substantial intra and inter patient variability

Page 4: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #4

Issues for dosing of ART in children

Large variability in pharmacokinetic (PK) parameters

– age (and PK data by age-group often sparse)

– effect of nutritional status

– ethnicity

Methods of dose calculation (per m2 or per kg)

Ability to give with/without food (ddI, NFV)

Page 5: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #5Impact of Nutrition on PK(Can have a profound effect)

Diminished protein status in malnourished children

results in lower plasma proteins

Increasing concentrations of ‘free’ drug

Severely malnourished children have decreased

CYP450 metabolism

Reduced hepatic clearance

Severely malnourished children have decreased GFR

Reduced renal clearance

Murry et al Int J Cancer 1998; 11: 48-51 Jorquera F et al Nutrition 1996; 12: 442-447

Page 6: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #6

Drug

ME3012.PPT

10

1

Time

Con

cent

ratio

n

Time

10

1C

once

ntra

tion

Drug

GCCCCACCTC

GCCCCGCCTC

A

B

P 450

P450

mutation

wild type

Mechanism of Genetic Variability in Drug ResponseSame dose but different plasma concentrations

AUC 1

AUC 20

Page 7: Paediatric Antiretroviral PK David Back University of Liverpool, UK

A Common CYP2B6 Variant Associated with EFV PK and CNS Side Effects

• A CYP2B6 polymorphism.

• More common in African-Americans than European-Americans.

• Associated with higher EFV levels, and increased CNS AE’s.

• Additional studies needed.

Slide #7

Page 8: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #8Patient 6: 40 yrs cauc man primary infection

10

100

1000

10000

0 100 200 300 400 500 600

Time after stopping EFV (h)

EF

V c

on

c n

g/m

l (l

og

sca

le)

10

100

1000

10000

100000

vira

l lo

ad c

op

ies/

ml l

og

sca

le

T1/2 50.7 h

CBV

1 w k 2 w k 3 w k

Resistance WT at wk 6

S. Taylor et al. 11th CROI Abs 131

Page 9: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #9Patient 9: 32 yrs African woman Toxicity

10

100

1000

10000

0 100 200 300 400 500 600

Time after stopping EFV (h)

efv

con

c n

g/m

l( (

log

sca

le)

10

100

1000

10000

100000

Vir

al l

oad

co

pie

s/m

l (l

og

sca

le)

CBV + NVP 10 days

T1/2 228.6 h

1 wk 2 wk 3 wk

S. Taylor et al. 11th CROI Abs 131

Page 10: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #10Note: Difference between plasma and intracellular half life

Time (hours)

0 5 10 15 20 251

10

100

1000

10000

IntracellularCarbovir-TPt1/2 20.64h

Plasma Abacavirt1/2 2.59 h

Plasma Abacavir, ng/mL

Intracellular CBV-TP, fmol/million cell

Piliero P, et al. 43rd ICAAC 2003, Abstr. A-1797

Page 11: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #11

ZDVTP 7 h NVP 25-30 h

d4TTP 7 h EFV 35 h

3TCTP 16 h

CBVTP 20 h

ddATP 25 h

TDFDP 60 h

FTCTP 39 h

NRTI (intracellular) and NNRTI half lives

Page 12: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #12

Balancing drugs with different half lives

0 24 483612

Time (hours)

Dru

g c

on

cen

trat

ion

Zone of potential replication

IC90

IC50

Last Dose

Day 1 Day 2

MONOTHERAPY

S. Taylor et al. 11th CROI Abs 131

Page 13: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #13

3TC Clearance in Children

Sokol E, et al. AAC 2000, 44:590-97Sokol E, et al. AAC 2000, 44:590-97

Page 14: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #14

NVP Concentrations in Children by Age

< 2 years 2-8 years > 8 years0

2500

5000

7500

10000

12500

15000

17500

20000

22500N

VP

Co

nce

ntr

atio

n (

ng

/ml)

Page 15: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #15Paediatric Nevirapine Concentrations(twice daily regimens)

10

100

1000

10000

100000

0 4 8 12 16 20 24

Time post dose (h)

Pla

sma

Nev

irap

ine

(ng

/ml)

3400 ng/ml

26.0% (20/77) below target

Page 16: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #16Paediatric Nevirapine Concentrations(twice daily regimens)

10

100

1000

10000

100000

0 4 8 12 16 20 24

Time post dose (h)

Pla

sma

Nev

irap

ine

(ng

/ml)

8000 ng/ml

23.4% (18/77) 23.4% (18/77) above targetabove target

Page 17: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #17

Nelfinavir PK in Children

Age <2 y

(n=7) >2 y

(n=17)

Cmax (µg/ml) 2.2 3.6

Cmin (µg/ml) 0.43 0.69

AUC (µg/ml.h) 11.2 15.0

Children <2 y at risk of subtherapeutic NFV levels

Bergshoeff et al, 2002

Page 18: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #18Nelfinavir Troughs with TID and BID Dosing

* Gatti G, et al. Clin Infect Dis, 2003;36:1476-82.* Gatti G, et al. Clin Infect Dis, 2003;36:1476-82.

NFV PK were evaluated in 35 children (8.1 ± 3.5 yrs) receiving 20-30 mg/kg q8h or 50 mg/kg q12 h with food.

Trough values were:

– 1.55 mg/L (0.13-5.22 mg/L) for TID dosing

– 1.11 mg/L (nd-6.08 mg/L) with BID.

1/11 (9%) in TID group vs. 7/14 (50%) in BID group had values < 1 mg/L (p=0.042).

Page 19: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #19

Nelfinavir Use in Children

The proportion of children 2-13 years of age achieving an HIV RNA level < 400 cpm through 48 wks ranged from 26-42%.

Response rates in children < 2 years of age appeared to be poorer than those ≥ 2 years.

Highly variable exposure remains a significant problem in the use of nelfinavir in pediatric patients.

Viracept Package Insert, March 29, 2004Viracept Package Insert, March 29, 2004

Page 20: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #20

LPV Concentrations in Children by Age

< 2 years 2-8 years > 8 years0

10000

20000

30000

40000

50000

LP

V C

on

cen

trat

ion

(n

g/m

l)

Page 21: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #21Lopinavir/r (300/75 mg/m2 BID) Pharmacokinetics in Children

All Subjects (N=27)

No NVP (5 ≤ 2 yrs)

With NVP (2 ≤ 2 yrs)

Tmax (h) 4 ± 2.1 4 ± 2 4 ± 2.3

Cmax (mg/L) 11.4 ± 4.9 12.5 ± 5.8 10.0 ± 3.3

Cmin (mg/L) 5.2 ± 4.3 6.53 ± 4.6 3.6 ± 3.5

Cpre (mg/L) 6.9 ± 4.1 7.9 ± 4.5 5.6 ± 3.3

AUC12 (mg•h/L)

102.8 ± 50.7 116.4 ± 57.1 85.8 ± 36.9

T1/2 (h) 6.1 ± 5.2 7.6 ± 5.1 4.7 ± 4.5

X. Saez-Llorens et al. Ped Infect Dis J 2003;22:216-23.

Page 22: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #22Reduced Lopinavir Plasma Concentrations in Pregnancy

Stek et al. Abstract LBOrB08.

0123456789

10

0 1 2 3 4 5 6 7 8 9 10 11 12Time Post Dose (hours)

Med

ian

SE

) L

op

inav

ir (

μg

/mL

)

13

Pregnancy (n = 17) Postpartum (n = 8) Nonpregnant historical controls

Note also abstract 4644 – NVP plasma exposure reduced in pregnant vs nonpregnant women

Protein-adjusted IC50 for LPV

Page 23: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #23Key Points Incomplete knowledge of pharmacology

Marked Inter individual variability

Nutritional status & PK

Age group & PK

Ethnicity & PK

Dosing according to weight or BSA seems arbitary.

Equivalence – Pharmaceutic & Bioequivalence

Bd vs qd

The future of PIs in children

1st line to ?????

Page 24: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #24

Page 25: Paediatric Antiretroviral PK David Back University of Liverpool, UK

Slide #25

Nelfinavir Pharmacokinetics in Children vs. Adults