Physiologically based pharmacokinetic (PBPK) model to predict the magnitude of drug-drug interaction between vincristine and the azole antifungals isavuconazole, posaconazole, and voriconazole in children

ABSTRACT Invasive fungal diseases (IFDs), including invasive aspergillosis (IA) and invasive mucormycosis (IM), occur primarily in immunocompromised and/or hospitalized patients and are associated with increased morbidity and mortality. Isavuconazole and posaconazole are triazole compounds approved for the treatment of IA/IM in adults and children, while voriconazole is approved for IA treatment only. All triazole compounds inhibit CYP3A, and both isavuconazole and posaconazole inhibit the transporter P-gp. Pediatric patients being treated for leukemia with vincristine frequently experience fungal infections, requiring treatment. Vincristine is metabolized by CYP3A4 and CYP3A5 and eliminated via P-gp transport. The risk of drug-drug interactions (DDIs) between vincristine and triazole compounds is known; however, the magnitude of risk has not been quantified. In the present analysis, physiologically based pharmacokinetic (PBPK) models were built for the triazoles and vincristine in a pediatric cancer population using the Simcyp simulator and were used to predict the change in vincristine exposure following coadministration with triazoles. Different age groups and CYP3A5 phenotypes were also explored. Modeling predicted that vincristine geometric mean AUC inf ratios in CYP3A5 poor metabolizers (PMs) ranged from 2.01- to 2.25-fold, 4.97- to 5.20-fold, and 1.43- to 1.53-fold with isavuconazole, posaconazole, and voriconazole, respectively. In CYP3A5 extensive metabolizers (EMs), vincristine AUC inf ratios ranged from 1.22- to 1.38-fold, 1.19- to 1.24-fold, and 1.05- to 1.07-fold for isavuconazole, posaconazole, and voriconazole, respectively. The model predicted vincristine AUC inf >100 ng·h/mL in CYP3A5 PM and <100 ng·h/mL in CYP3A5 EM; therefore, vincristine dose reduction may be required only in CYP3A5 null expressors.