Azole Therapeutic Drug Monitoring

1. Azole Therapeutic Drug Monitoring Chris Kosmidis National Aspergillosis Centre, Manchester, UK

2. Learning Objectives To understand the reasons for therapeutic drug monitoring (TDM) To discuss the different methods of TDM To review the evidence for TDM for itraconazole and voriconazole

3. Why do we need TDM for azoles? • Interacting drugs • proton pump inhibitors inhibit itraconazole capsule absorption • rifampicin increases azole metabolism, resulting in undetectable azole levels • Compliance • to confirm therapeutic levels. Important for long-term therapy • Severe disease • e.g. central nervous system aspergillosis: to make sure adequate levels are reached • Pharmacokinetic variability • children, elderly, obese • critical illness, organ failure • Itraconazole and voriconazole have unpredictable PK and need TDM • No need for fluconazole TDM

4. Which TDM method to use? • Bioassay • Cheap, simple • Other antifungals may interfere with results • Measures combined itraconazole and its metabolite • HPLC • Widely available • Can detect multiple drugs in one sample • Measures itraconazole separate from its metabolite • Mass spectrometry • Expensive • Detects multiple drugs in one sample • Very sensitive and specific

5. Itraconazole

6. Itraconazole Hydroxy-itraconazole Itraconazole • Oral solution 30% more bioavailable than capsules • Capsules need to be taken with food and acidic beverage to improve absorption. Proton pump inhibitors will reduce absorption of capsules • Oral solution preferably on empty stomach • Steady state reached after 1-2 weeks of therapy • Hydroxy-itraconazole metabolite has comparable activity • Bioassay will detect both hydroxy-itraconazole and itraconazole • HPLC will detect itraconazole only

7. Itraconazole levels and risk of fungal infection Capsules Meta-analysis of 3500 cases of neutropenic patients on itraconazole prophylaxis Trough levels of <0.5 mg/L (HPLC) associated with higher mortality Only itraconazole suspension prevented invasive aspergillosis Solution Total Favours control Favours itraconazole Glasmacheret al, J ClinOncol 2003;21:4615

8. Itraconazole levels and toxicity A level of 17.1 mg/L by bioassay was the best predictor of toxicity Lestneret al, Clin Infect Dis 2009;49:928

9. Itraconazole recommendations • Recommended range on bioassay: 5-17 mg/L • Recommended range on HPLC: 1-3 mg/L • Levels can be random (not trough) • If level above range, reduce total daily dose by 100-200 mg per day • If level below range: • Check compliance and interactions • Increase total daily dose by 100-200 mg • Stop proton pump inhibitors if possible • Administer capsules with food and cola or other acidic beverage • Switch capsules to liquid

10. Voriconazole

11. Voriconazole • Non-linear PK, dose changes may have unpredictable effects and result in very high levels • Oral bioavailability >80% (lower in children) • Take on empty stomach • Omeprazole may increase levels to a small extent • Polymorphisms in CYP2C19 result in wide variability in clearance • Up to 30% of Asians may have significantly low 2C19 activity, so more likely to have toxic levels • Children will metabolise faster through 2C19: higher doses needed in children • Better outcomes when levels measured • Toxicity is dose-related

12. Voriconazole TDM and outcomes • Several studies show correlation between levels and outcome • Prospective randomised study of TDM vs non-TDM for voriconazole (Park et al Clin Infect Dis 2012:55:1080): • In TDM group, levels were kept between 1-5.5 mg/L • Fewer discontinuations in the TDM group (4% vs 17%) • Better response in the TDM group (81% vs 57%)

13. Voriconazole: Relation of exposure to neurotoxicity Levels >5.5 mg/L, 5/16 had neurotoxicity vs none when level <5.5 mg/L Pascual et al, Clin Infect Dis 2008;46:201

14. Voriconazole: Relationship of exposure to liver abnormalities Matsumoto et al, Int J Antimicrob Ag 2009;34:91

15. Voriconazole recommendations • Target trough level >1 mg/L to improve efficacy • Aim for level >2 mg/L for severe infections • Target trough level <5.5 mg/L to minimise toxicity • Measure within 5 days of starting, after change from IV to oral, or with change in dose

16. Voriconazole recommendations • If level above range: • Reduce by 50%. • If levels very high (>10 mg/L): • Consider alternative antifungal • Or skip one dose and reduce by 50% • If level below range: • Check compliance and interactions • Increase by up to 50% (e.g. 50-100 mg twice daily if oral) • Consider alternative antifungal if already on >350 mg twice daily • Recheck within 5 days as response may be unpredictable

17. Other antifungals • Posaconazolesuspension • Better absorbed with fatty meal • Aim level >0.7 mg/L for prophylaxis or >1 mg/L for treatment • Aim <3.75 mg/L • Posaconazoletablets • Much better absorption, no food requirements • Usually result in higher levels • Isavuconazoletablets • No current guidance for TDM

18. Summary Itraconazole and voriconazole are the main azoles that require TDM TDM can reduce toxicity and enhance efficacy of antifungal therapy

19. Thank you