Advances Against Aspergillosis Istanbul, 2012 Anti-fungal therapeutic drug monitoring and azole dose...

Advances Against AspergillosisIstanbul, 2012

Anti-fungal therapeutic drug monitoring and azole dose

modification

Tim Felton

Contents

• Triazoles – an overview

• Therapeutic drug monitoring (TDM)

• Specific drugs

Triazoles• Bind cytochrome P450-enzyme lanosterol 14-

demethylase• Inhibits the conversion of lanosterol to ergosterol• Fluconazole• Itraconazole• Voriconazole• Posaconazole• (Isavuconazole)

Response

Toxicity

2 3 4 5 6 7 8

Drug exposure

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (hours)

Peak Concentration

Time>threshold

Exposure

Indications for TDM1. Variable pharmacokinetics

PK-PD: the black artsDOSE

0.01 0.1 1 10 100 1000

Total dose 5FC (mg/kg)

log 10

BIOMARKER OUTCOME OF CLINICAL INTEREST/IMPORTANCE

•Survival

•Resolution of clinical syndrome

•Quantifiable•Linked to pathogenesis•Linked to an outcome of clinical interest

PHARMACOKINETICS PHARMACODYNAMICS

Pharmacokinetic variability

0 24 48 72 96 120 144 168

Time (hours)

Sub-therapeutic

Time (hours)

Hope WW. AAC. 2012. In press

Howard S. TDM. 2012. 34:72-76

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

0 96 192 288 384 480

Time (hours)

Extensive Metaboliser

Poor Metaboliser

Pharmacogenomics

Absorption

Time (hours)

Suspension (fasted)

Suspension (high-fat meal)Suspension (non-fat meal)

Courtney R . Br J Clin Pharmacol 2004:218–222.

0 29 58 87 116 145 174 203 232 261 290 319 348

Time (hours)

Saturation of metabolism

Dosage escalation from 200 mg bd to 300 mg bd

2. Clinically relevant exposure–response relationships

Experimental IPA in rabbits

Berenguar et al, AAC 1994;38:1303-8

Hope WW AAC. 2012. 56:526-31.

Exposure-trough conc.

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)

Effect

3. Clinically relevant exposure–toxicity relationships

Lestner J M. CID. 2009. 49:928-930

Concentration-toxicity

Clinical IPA

0 1 2 3 4 5 6 7 8 9 10

Effect Toxicity

4. Narrow therapeutic window

Clinical IPA

0 1 2 3 4 5 6 7 8 9 10

Effect Toxicity

5. Unable to rapidly assess response

6. Serious/poor prognostic disease

7. Drug–drug interactions

8. Compliance

9. Dosage adjustment

Specific dugs• Fluconazole• Itraconazole• Voriconazole• Posaconazole

• Indication• Pharmacology/pharmacokinetics• Exposure–response relationship • Exposure–toxicity relationship• TDM target

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

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

Itraconazole• Indication

– Prophylaxis of IFI– Treatment of IPA– Treatment of CPA – Treatment of ABPA

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

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)

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

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!

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!

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

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

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

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

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

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

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

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

5. Unable to rapidly assess response

6. Serious/poor prognostic disease

7. Drug–drug interactions

8. Compliance

9. Dosage adjustment

Response

Toxicity

2 3 4 5 6 7 8

Drug exposure

Conclusions• TDM required for itraconazole and voriconazole• Probably for posaconazole• TDM should

– Improve outcomes– Reduce emergence of resistance– BUT there is an associated cost

Advances Against Aspergillosis Istanbul, 2012 Anti-fungal therapeutic drug monitoring and azole dose...

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