Physiologically-based pharmacokinetic model for predicting drug-drug interactions perpetrated by posaconazole in healthy subjects with normal weight and obesity: Concomitant use and washout

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Abstract
Posaconazole is an effective broad-spectrum triazole antifungal used as prophylaxis or to treat invasive Aspergillus and Candida infections in adults and pediatric patients. Posaconazole is a known strong inhibitor of cytochrome P4503A4 (CYP3A4) and substrate of P-glycoprotein (P-gp), which may lead to drug-drug interactions (DDIs) when co-administered with CYP3A4-sensitive substrates and warrants modified dosing of sensitive drugs when administered concomitantly with posaconazole. Given the long elimination half-life of posaconazole (26-35 h), there is the potential for DDIs caused by posaconazole after discontinuing the antifungal. Our clinical studies revealed that the half-life of posaconazole is significantly prolonged in subjects with a body mass index (BMI) ≥ 35 kg/m2, which may put this population at an increased risk of DDIs after stopping posaconazole. This manuscript describes the development, verification, and validation of a whole-body, physiologically-based pharmacokinetic (PBPK) model which describes the concomitant use and washout DDIs of posaconazole delayed-release tablet (DRT) with victim drugs ranolazine and lurasidone in healthy volunteers of normal weight and with obesity. The key findings of this model are 1) the half-life of posaconazole is significantly prolonged in patients with BMI ≥ 35 kg/m2 and 2) the mechanism of inhibition of CYP3A4 by posaconazole appears to be irreversible in vivo. This model may be used moving forward to assess the potential for washout DDIs with CYP3A4-sensitive substrates during concomitant use with, and after discontinuing posaconazole in subjects with normal weight and obesity.
Funding Information
  • National Institutes of Health (UM1TR004398)

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