Biotransformation and elimination. After administration of the posaconazole suspension, 77% of the dose is excreted by feces of which >66% is unchanged, while 13% of the doses is eliminated in urine of which <0.2% is unchanged [2]. Unlike other triazole antifungal agents, posaconazole is barely metabolized by cytochrome P450 (CYP). About 17% is glucuronidated by UGT1A4 and the remainder is eliminated unchanged [69, 70]. There are no major circulating metabolites. Nevertheless, posaconazole may still be impacted as victim drug by interactions with drugs that interact with UGT enzymes, like phenytoin, rifampin, and fosamprenavir [2]. Besides that, posaconazole is a potent inhibitor of CYP3A4 [2]. Clinicians and pharmacists should remember that the inhibitory potency of posaconazole is concentration, and thus formulation, dependent [71]. Several clinically relevant drug-drug interactions have been identified that require substantial empirical dose reductions of victim drugs (i.e. 30 - 50%), like cyclosporine A or tacrolimus. Adding to these examples are the interactions of posaconazole with new targeted therapies such as ibrutinib, venetoclax and ruxolitinib that make optimal management with these combinations challenging [72]. The posaconzole intravenous injection showed a decrease in clearance when increasing a single dose from 50 mg to 200 mg and this remained stable for doses of 200 mg and 300 mg [29]. which may be attributable to saturation of for instance enzyme or transporter involved in the elimination of posaconazole, which leads to the observed more-than-dose-proportional increase in exposure. Posaconazole clearance (CL) reported in a population pharmacokinetic analysis using combined data from both healthy volunteers and patients with AML/MDS/HSCT receiving an intravenous infusion appeared to be in line with these results reported from a clinical pharmacokinetic study in healthy volunteers (7.8 vs. 6.5 - 6.9 L/h) [29, 30]. The apparent clearance (CL/F) observed upon administration of the posaconazole suspension in patients is significantly higher than in healthy volunteers and differs among different patient populations. Patients with persistent febrile neutropenia or refractory IFD, patients from SICU, and cystic fibrosis patients after lung transplantation appear to have high CL/F values (283.0, 195.0 and 143.2 L/h, respectively) [27, 36, 54], compared with those suffering from AML/MDS/HSCT (42.5 - 67.0 L/h) [35, 37, 38]. In general, the difference in F plays an important role in ...
