Pharmacokinetic-pharmacodynamic optimization of triazole antifungal therapy

Purpose of review Pharmacokinetic and pharmacodynamic properties of antifungal drugs are two factors affecting outcome of invasive fungal infections. This review examines the pharmacokinetic/pharmacodynamic properties of triazoles, approaches to optimizing triazole pharmacokinetics/pharmacodynamics to improve outcomes, and the rationale for therapeutic drug monitoring of itraconazole, voriconazole, and posaconazole. Recent findings Fluconazole and voriconazole are readily absorbed and exhibit high oral bioavailability, whereas the oral bioavailability of itraconazole and posaconazole is generally lower and more variable. Posaconazole absorption is dependent on administration with a high-fat meal or nutritional supplement. Lack of gastric acidity negatively impacts absorption of posaconazole suspension or itraconazole capsules. Itraconazole and voriconazole undergo extensive hepatic metabolism involving the cytochrome P450 (CYP) system, whereas posaconazole undergoes minor glucuronidation. All triazoles inhibit CYP3A4 to varying degrees. Drug levels of the various triazoles can be optimized by attending to pharmacokinetic-altering factors (e.g., administering posaconazole with a high-fat meal/supplement and avoiding or making adjustments for coadministration of drugs affecting their metabolism). Itraconazole, voriconazole, and posaconazole exhibit wide and sometimes unpredictable pharmacokinetic variability. This, together with a relatively narrow and reasonably defined therapeutic range, makes these agents prime candidates for therapeutic drug monitoring. Summary By attending to factors altering pharmacokinetics, blood levels of the respective triazoles can be optimized for efficacy and safety. Under certain circumstances, therapeutic drug monitoring can play an important role in identifying patients at risk for treatment failure or toxicity, and guide dosing in pharmacokinetically complex patients.