The role of antifungal therapeutic drug monitoring (TDM)? Dr Livingstone Chishimba BSc, MBChB, MRCP University Hospital of South Manchester The University of Manchester

Outline PK affects the antifungal effect Implications of TDM Potential indications for TDM-general Implications of TDM Itra,vori, posa, Efficacy and safety Studies and evidence Clinical implication

Issues Why monitoring? Who to monitor? What? When? Where ? What action? clinically relevant ? exposure–response relationships exposure–toxicity relationships

TDM-which drugs?-general compounds with ; a narrow therapeutic window Warfarin, theophyllins variable pharmacokinetics (PK) itra physiological instability

Clinical objectives of TDM Optimise efficacy Minimise toxicity Hope WW et al. Curr Opin Infect Dis 2008; 21: 580

Clinical use of TDM drug-drug interactions check compliance change of dosage patient failing therapy

Antifungal TDM Itraconazole Voriconazole Posaconazole

Itraconazole Itraconazole

Two formulations of itraconazole Excipients differ between generic formulations, and systemic exposure may differ Capsules Cyclodextrin excipient 20-50% higher bioavailability Suspension

Itraconazole exhibits nonlinear PK Time to steady state ~14 days Once linear clearance achieved, t1/2 ~24 hours Itraconazole, ng/mL plasma Hours Barone JA et al. Antimicrob Agents Chemother 1993; 37: 778

Itraconazole: PK and variability Itraconazole poorly soluble at physiological pH Absorption of itraconazole tablets is variable; requires acidic environment, which is often absent in critically ill patients Increased bioavailability with food and cola Itraconazole suspension is often poorly tolerated (gastrointestinal), leading to compliance problems

Variability in itraconazole PK affects the antifungal effect Significant relationship between drug level and fungal burden Pulmonary fungal burden Peak itraconazole concentrations (mg/L) Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

Itraconazole: dose-response relationship in rabbits with IA Berenguar et al, AAC 1994;38:1303-8

Itraconazole: incidence of proven invasive fungal infections Capsules Itraconazole trough concentrations of <0.5 mg/L associated with higher mortality (p= 0.039) Easier to get better levels with suspension Solution Total Favours itraconazole Favours control Glasmacher et al JCO 2003

Toxicity and itraconazole concentrations Itraconazole concentration mg/L Probability of toxicity (%) NOTE that the highest quintile consists of values ≥ 25.6 mg/L. The line is a logistic regression fit to the individual measurements. 5 10 15 20 25 100 80 60 40 Lestner, Clin Infect Dis 2009 In press

Itraconazole: concentration-toxicity relationship 216 patients mostly capsules Probability of toxicity A range of AE, most common: Fluid retention Gastrointestinal intolerance Trough itraconazole concentrations (mg/L) Lestner JM et al. Clin Infect Dis 2009; 49: 928

Itraconazole: concentration-toxicity relationship Probability of toxicity Probability of toxicity low<17.1>high Trough itraconazole concentrations (mg/L) Lestner JM et al. Clin Infect Dis 2009; 49: 928

Voriconazole

Voriconazole Displays nonlinear PK in adults, with saturable clearance Disproportionate changes when dose altered ~5 days to achieve steady state concentrations Exhibits linear PK in children Children may metabolise more quickly Dose escalation may be required Trifilio SM et al. Antimicrob Agents Chemother 2009; 53: 1793 Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166

Voriconazole - metabolism 98% metabolised by liver Primarily metabolised by CYP2C19 and CYP3A4, less by CYP2C9. Genotype status for CYP2C19 and/or co-administration of drugs that modulate CYP2C19 or CYP3A4 activities do affect voriconazole plasma levels. PC BRASS, OAK DEVICESS 3-5% caucasians, 15-20% Asians have genetic polymorphism of CYP2C19 - slow metabolisers Cirrhosis / prior alcohol abuse, likely predictors of slow metabolisers Voriconazole datasheet

Therapeutic drug monitoring may be useful to optimise therapy for individual patients A “fast’ metaboliser with relatively low concentrations, who is failing therapy Dosage escalation from 200 mg bd to 300 mg bd

A “slow’ metaboliser: dosage escalation may be too risky and this could be prevented with TDM Dosage escalation from 200 mg bd to 300 mg bd

Voriconazole: exposure-response relationships There have been REAL difficulties linking drug exposure with effect because: Good PK was not done in the trials (trough, random, mean levels) Assessing patient outcome is really tough Random levels of < 2.05 mg/L associated with poorer outcome (Smith et al AAC 2006) 15% of patients in recent studies have no detectable levels of drug in serum! (Trifilio et al 2007)

Efficacy and safety of voriconazole 26 patients (ABPA, n=21, SAFS=5) Poor relationship between dose and Clinical efficacy ?Good relationship between Dose, TDL and AEs Chishimba L, denning D et al 2011 (unpublished data) Chishimba L, denning D et al 2011 (unpublished data)

Chishimba L, denning D et al 2011 (unpublished data)

Posaconazole

Posaconazole Saturation of absorption above 800mg/day Displays linear PK with dosages of 50-800mg Saturation of absorption above 800mg/day ~7-10 days to achieve steady state concentrations Minimal differences between peak and trough levels Similar blood concentrations found in juveniles with comparable efficacy and safety Courtney R et al. Antimicrob Agents Chemother 2003; 47: 2788 Krishna G et al. Antimicrob Agents Chemother 2007; 51: 812

Posaconazole as salvage therapy for invasive aspergillosis: exposure-response relationship Walsh TJ et al. Clin Infect Dis 2007; 44: 2

Posaconazole: concentration-response relationship from prophylaxis studies Clinical failure of 25% at levels of 0.71mg/L Clinical failure: death fungal infection drug stopped use of other antifungals http://www.fda/cder/foi/nda/2006/022003s000_Noxafil_ClinPharR.pdf. 2005

Antifungal TDM-Which drug to monitor? Necessary Itraconazole Voriconazole (especially IV, children, complex case) Flucytosine

Antifungal TDM-Which to drug to monitor? Unnecessary Amphotericin B Echinocandins (not much data though) Fluconazole (unless short gut and oral administration, or compliance) Desirable Posaconazole (probably)

Itraconazole TDM: clinical practice Targets HPLC: >0.5 mg/L Bioassay >5 mg/L Low levels with capsules usually due to suboptimal absorption Administer with food or cola Stop H2 antagonists, PPIs Check for drug interactions (rifampicin, phenytoin, carbamazepine). Can increase from 200 mg b.i.d to 300 mg b.i.d Change to suspension Monitor compliance Understand variance

Voriconazole TDM in clinical practice Target: pre-dose (only) should be monitored greater than 1.0 and less than ~5.5mg/L Monitor for duration of therapy Give loading dose preferably iv Look for and expect nonlinear behaviour when adjusting dose

Posaconazole TDM in clinical practice Targets not well defined Trough >0.5mg/L prophylaxis Trough 0.5-1.5mg/L therapy Absorption affected by a number of factors: frequency of dosage (saturable) food, gastric pH and mucosal health Side effects: insufficient data to determine if dose-dependent To increase levels: may not be any benefit going >800mg/day fractionate dose give with fatty food Andes D et al. Antimicrob Agents Chemother 2009; 53: 24

Take home message Linear PK: itra and posa None linear PK: vori Dose alteration not only on TDL but on clinical response, Aes Consider drug interactions PPI, antiepileptics , macrolides time-diet timing etc if not able to achieve TDL but clinical outcome most important. frequency of dosage (saturable) food, gastric pH and mucosal health but much more work required using population PK modelling to reach the goal of truly individualising therapy!