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Advances Against AspergillosisIstanbul, 2012
Anti-fungal therapeutic drug monitoring and azole dose
modification
Tim Felton
Advances Against AspergillosisIstanbul, 2012
Contents
• Triazoles – an overview
• Therapeutic drug monitoring (TDM)
• Specific drugs
Advances Against AspergillosisIstanbul, 2012
Triazoles• Bind cytochrome P450-enzyme lanosterol 14-
demethylase• Inhibits the conversion of lanosterol to ergosterol• Fluconazole• Itraconazole• Voriconazole• Posaconazole• (Isavuconazole)
Advances Against AspergillosisIstanbul, 2012
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Response
Toxicity
2 3 4 5 6 7 8
Drug exposure
Pro
ba
bil
ity
Advances Against AspergillosisIstanbul, 2012
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hours)
0.00
0.40
0.80
1.20
Dru
g C
once
ntra
tion
(mg/
L)
Peak Concentration
Time>threshold
AUC
Exposure
MIC
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
Advances Against AspergillosisIstanbul, 2012
PK-PD: the black artsDOSE
0.01 0.1 1 10 100 1000
Total dose 5FC (mg/kg)
0
1
2
3
4
5
6
7
Effe
ct (
log 10
CF
U/g
)
BIOMARKER OUTCOME OF CLINICAL INTEREST/IMPORTANCE
•Survival
•Resolution of clinical syndrome
•Quantifiable•Linked to pathogenesis•Linked to an outcome of clinical interest
PHARMACOKINETICS PHARMACODYNAMICS
Conc
Dose
Advances Against AspergillosisIstanbul, 2012
Pharmacokinetic variability
0 24 48 72 96 120 144 168
Time (hours)
0
2
4
6
8
10
12
14
16
18
20
Vor
icon
azol
e C
once
ntra
tions
(m
g/L)
Toxic
Sub-therapeutic
Vor
icon
azol
e C
once
ntra
tion
(mg/
L)
Time (hours)
Advances Against AspergillosisIstanbul, 2012
Hope WW. AAC. 2012. In press
Pharmacokinetic variability
Advances Against AspergillosisIstanbul, 2012
Howard S. TDM. 2012. 34:72-76
Pharmacokinetic variability
Advances Against AspergillosisIstanbul, 2012
Pharmacokinetic variability• Absorption
– Vomiting– Diet– Genetic differences in drug-
transport/gut-metabolism– Concomitant medications
• Distribution– Amount of body fat– Presence of extravascular
fluid collections– Hypoalbuminaemia
• Metabolism– Hepatic dysfunction– Genetic differences in drug-
metabolism– Concomitant medications
• Excretion– Hepatic dysfunction– Renal insufficiency– Genetic differences in drug-
elimination pathways
Advances Against AspergillosisIstanbul, 2012
0 96 192 288 384 480
Time (hours)
0
1
2
3
4
5
6
7
8
9
Vor
icon
azol
e C
once
ntra
tion
(mg/
L)
Extensive Metaboliser
Poor Metaboliser
Pharmacogenomics
Advances Against AspergillosisIstanbul, 2012
Absorption
Time (hours)
Suspension (fasted)
Suspension (high-fat meal)Suspension (non-fat meal)
Courtney R . Br J Clin Pharmacol 2004:218–222.
Advances Against AspergillosisIstanbul, 2012
0 29 58 87 116 145 174 203 232 261 290 319 348
Time (hours)
0
1
2
3
4
5
6
7
8
9
Vor
icon
azol
e C
once
ntra
tion
(mg/
L)
Saturation of metabolism
Dosage escalation from 200 mg bd to 300 mg bd
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
Advances Against AspergillosisIstanbul, 2012
Experimental IPA in rabbits
Berenguar et al, AAC 1994;38:1303-8
Advances Against AspergillosisIstanbul, 2012
Hope WW AAC. 2012. 56:526-31.
Exposure-trough conc.
Advances Against AspergillosisIstanbul, 2012
Clinical IPA
Pascual et al. CID. 2008. 46:201-11
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
eff
ect
Effect
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
Advances Against AspergillosisIstanbul, 2012
Lestner J M. CID. 2009. 49:928-930
Concentration-toxicity
Advances Against AspergillosisIstanbul, 2012
Clinical IPA
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
eff
ect
or t
oxic
ity
Effect Toxicity
Pascual et al. CID. 2008. 46:201-11
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
4. Narrow therapeutic window
Advances Against AspergillosisIstanbul, 2012
Clinical IPA
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
bab
ility
eff
ect
or t
oxic
ity
Effect Toxicity
Pascual et al. CID. 2008. 46:201-11
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
4. Narrow therapeutic window
5. Unable to rapidly assess response
6. Serious/poor prognostic disease
7. Drug–drug interactions
8. Compliance
9. Dosage adjustment
Advances Against AspergillosisIstanbul, 2012
Specific dugs• Fluconazole• Itraconazole• Voriconazole• Posaconazole
• Indication• Pharmacology/pharmacokinetics• Exposure–response relationship • Exposure–toxicity relationship• TDM target
Advances Against AspergillosisIstanbul, 2012
Fluconazole• Indication
– Prophylaxis– Empirical therapy– Treatment of superficial and invasive candidiasis
• Pharmacology/pharmacokinetics– Linear PK– High bioavailability
• Exposure–response relationship– Well defined
Rodríguez-Tudela J L. AAC. 2007. 51:3599-3604
Advances Against AspergillosisIstanbul, 2012
Fluconazole• Exposure–toxicity relationship
– High LFTs, nausea, vomiting, seizures at high dosages
• TDM target– Wide therapeutic index– Treatment of isolates with reduced susceptibility– Poor absorption – Paediatric patients
Advances Against AspergillosisIstanbul, 2012
Itraconazole• Indication
– Prophylaxis of IFI– Treatment of IPA– Treatment of CPA – Treatment of ABPA
Advances Against AspergillosisIstanbul, 2012
Itraconazole• Pharmacology/pharmacokinetics
– Highly lipophilic and protein bound capsule solubility in acidic environment– Different manufactures' capsules behave differently absorption with PPI and H2-antagonists
– Suspension (cyclodextrin) 20-50% higher bioavailability– Non-linear (probably)– Extensive variability– Active metabolite (OH-itraconazole) (bioassay/HPLC)– CYP3A4
Advances Against AspergillosisIstanbul, 2012
Itraconazole• Exposure–response relationship
– Peak itraconazole levels and successful outcome of mucosal candidiasis in patients with AIDS
– In vivo data• Exposure–toxicity relationship
– Gastrointestinal intolerance, hypokalaemia, fatigue, ankle oedema, cardiac failure and deranged LFTs
– Nausea more common with suspension (cyclodextrin)
Advances Against AspergillosisIstanbul, 2012
Itraconazole• TDM target
– 200mg b.i.d.– Trough concentration– Lower level
• Prophylaxis in neutropenia & treatment of oesophageal candidasis in HIV
• 0.5mg/L HPLC or 5mg/L bioassay– Upper level
• 17mg/L (bioassay)due to high probability of toxicity
Advances Against AspergillosisIstanbul, 2012
Itraconazole• Tips to improve low levels
– Usually poor absorption
1. Capsule with food or acid drink?
2. Stop PPI or H2-antagonist (if possible)
3. Compliance
4. Consistently prescribe the same preparation
5. Check for drug interactions
6. Increase to capsule 300mg twice daily or change to suspension 200mg twice daily
7. Check serum levels again!
Advances Against AspergillosisIstanbul, 2012
Itraconazole• Tips to reduce high levels +/- toxicity
– Usually saturated clearance
1. Stop drug for 1-2 weeks
2. Re-start at a lower dose
3. Check serum levels again!
Advances Against AspergillosisIstanbul, 2012
Voriconazole• Indication
– Disseminated candidasis– IPA and CPA
• Pharmacology/pharmacokinetics– Excellent bioavailabilty (96%)– IV preparation – cyclodextrin (potentially nephrotoxic)– Marked PK variability (100-fold)– Sex, age and CYP2C19 genotype only partially explain– Weight important in paediatric patients– CYP2C19, 3A4 and 2C9 substrate
Herbrecht R. NEJM. 2002. 347:408-15
Advances Against AspergillosisIstanbul, 2012
Voriconazole• Exposure–response relationship
– In-vivo, in-vitro and clinical data
• Exposure–toxicity relationship
– Gradual increase in probability with increasing concentration
– Abnormal LFTs, visual disturbance, photosensitivity, confusion etc
Pascual et al. CID. 2008:46;201-11
Advances Against AspergillosisIstanbul, 2012
Voriconazole• TDM target
– 200mg b.i.d. (i.v. loading dose)– Trough concentration– Lower level
• Trough 1mg/L associated with 70% probability of success
– Upper level• Less well established• >6mg/L associated with high probability of CNS toxicity
and hepatitis
Advances Against AspergillosisIstanbul, 2012
Voriconazole• Tips on use
– Loading dose– Switch IV to oral
• Tips to improve low levels– Dosage escalation carefully by 50mg daily– Check levels every 1-2/52
• Tips to reduce high levels +/- toxicity– Stop for 1 week or by TDM then reduce dosage– Stop omeprazole– Check levels
Advances Against AspergillosisIstanbul, 2012
Posaconazole• Indication
– Salvage therapy IPA– Prophylaxis neutropenia and HSCT
• Pharmacology/pharmacokinetics– Only oral suspension– Linear PK to 800mg/day– Absorption saturated above 800mg/day– Better absorption with fatty food and low stomach pH– Long t½ with comparable average and trough levels– Variability
Felton TW. CID. 2010;51:1383-1391
Advances Against AspergillosisIstanbul, 2012
Posaconazole• Exposure–response relationship
– In-vivo (mouse IC and rabbit IPA)– Increased clinical response with increasing average and
trough concentration
• Exposure–toxicity relationship– GI intolerance, abnormal LFT – No dose dependent
Walsh T. CID. 2007. 44. 2-12
Advances Against AspergillosisIstanbul, 2012
Posaconazole• TDM target
– 400mg b.i.d– Trough concentration (but long t½ life) – Lower level
• >0.7mg/L• Higher might be better if formulation/cost allowed!
– Upper level • Not known/defined
Advances Against AspergillosisIstanbul, 2012
Posaconazole• Tips to improve low levels
– Fatty foods, milk or fatty food supplements– Stop enzyme inducers – Stop PPIs– Can try fractionating the regimen– Dosage escalation unhelpful above 800mg/day
Advances Against AspergillosisIstanbul, 2012
Indications for TDM1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
4. Narrow therapeutic window
5. Unable to rapidly assess response
6. Serious/poor prognostic disease
7. Drug–drug interactions
8. Compliance
9. Dosage adjustment
Advances Against AspergillosisIstanbul, 2012
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Response
Toxicity
2 3 4 5 6 7 8
Drug exposure
Pro
ba
bil
ity
Advances Against AspergillosisIstanbul, 2012
Conclusions• TDM required for itraconazole and voriconazole• Probably for posaconazole• TDM should
– Improve outcomes– Reduce emergence of resistance– BUT there is an associated cost