A Drug-Drug Interaction of Ainuovirine with Fluconazole in Healthy Adults and Dose Optimization Informed by Pharmacokinetics Modelling

Purpose: The study aimed to assess the drug-drug interaction (DDI) and safety of ainuovirine (a new-generation non-nucleoside reverse transcriptase inhibitor, primarily metabolized by CYP2C19) coadministered with fluconazole, a strong CYP2C19 inhibitor, in healthy adults. Methods: This was a multiple-dose, open-label, two-period, parallel, sequential study. In group A, 18 participants received ainuovirine (150 mg, q.d.) from day 1– 7 (Period 1), followed by coadministration with fluconazole (200 mg, q.d.) from day 8– 14 (Period 2). In group B, 18 participants received fluconazole (200 mg, q.d.) from day 1– 7 (Period 1), followed by coadministration with ainuovirine (150 mg, q.d.) from day 8– 14 (Period 2). A physiologically based pharmacokinetic (PBPK) model of ainuovirine predicted its DDI with fluconazole, incorporating population PK analysis. Results: In group A, when coadministered with fluconazole, geometric means of ainuovirine C max,ss , AUC 0– 24,ss increased up to 233.0% and 349.6%, respectively, versus ainuovirine alone. In group B, there were no apparent effects of ainuovirine on C max,ss , AUC 0– 24,ss and T max,ss for fluconazole. No death or grade ≥ 3 serious adverse events occurred. The predictive performance of the PBPK model for the interaction scenario is excellent, because the ratios of predicted-to-observed C max,ss and AUC 0–∞,ss are very close to 1.0, which provides high confidence in the model’s simulations for dose optimization. Conclusion: Coadministration with fluconazole significantly alters the steady-state PK of ainuovirine, but not conversely. The DDI PBPK model supports that dose reduction of ainuovirine is warranted for coadministration with fluconazole.