Population Pharmacokinetic Model Assessment of the Effects of Body Weight on Risk of Drug–Drug Interactions After Posaconazole Discontinuation

Posaconazole is a broad-spectrum triazole antifungal agent indicated for the prophylaxis and treatment of invasive fungal infections. Posaconazole pharmacokinetics and drug-drug interactions (DDIs), due to cytochrome P450 3A4 (CYP3A4) inhibition, have been previously characterized. This pharmacokinetic simulation study assessed whether the known weight-dependent effects on posaconazole pharmacokinetics could prolong the risk of CYP3A4-mediated DDIs following posaconazole discontinuation in persons with obesity. A population pharmacokinetic model developed from 1092 individuals showed 25% lower average steady-state posaconazole concentrations in individuals with body weight 120 kg versus 70 kg. Steady-state posaconazole concentration-time profiles following administrations of therapeutic doses and upon discontinuation of dosing were simulated across a range of body weights (70-180 kg). Simulated concentration-time profiles were evaluated against the in vitro CYP3A4 inhibition constant (K_i) for posaconazole in human hepatic microsomes, adjusted for plasma protein binding and fraction unbound in microsomes (K_iu). As expected, distribution patterns of posaconazole concentration-time profiles suggested differences between individuals with body weight ≥ 120 and < 120 kg. Following discontinuation, concentration-time profiles declined in a parallel manner at later timepoints, indicating a similar posaconazole half-life across body weights. Mean posaconazole concentrations fell below the K_iu of 844 ng/mL by approximately 3 days after discontinuation across all body weights, suggesting no differences in the potential for DDIs mediated through CYP3A4 beyond that timepoint. These findings indicate that the duration of clinically relevant posaconazole CYP3A4 inhibition is similar across body weights and support continued use of existing guidance on co-administration and discontinuation of posaconazole with CYP3A substrates.