Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects

Abstract

37

Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects

Li Linghua, Huang Jianfei, Lei Yan, Cai Weiping, Meng Yu, Xiao Lei, Zhao Yi, Lin Weitong, He Yaozu, Huang Kaipeng and Qin Hong

Guangzhou Eighth People's Hospital, Guangzhou Medical University

Introduction: Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for used in combination therapy for people living with HIV (PLWH) in China, which is metabolized by CYP2C19. The aim of this phase 1 study was to assess the drug–drug interaction (DDI) and safety of ainuovirine when co-administered with fluconazole, a strong CYP2C19 inhibitor, by experimentally obtained in healthy adult subjects and a physiologically based pharmacokinetics (PBPK) model was developed for dose prediction of ainuovirine.

Methods: This was a single-centre, open-label, parallel-group, fixed-sequence, two-period study in healthy subjects (aged 20–45 years). Thirty-six healthy subjects were allocated into two groups. In group A, 18 healthy subjects received oral ainuovirine (150 mg) once daily in period 1 (days 1–7), followed by co-administration with oral fluconazole (200 mg) once daily in period 2 (days 8–14). In group B, 18 healthy subjects received oral fluconazole (200 mg) once daily in period 1 (days 1–7), followed by co-administration with oral ainuovirine (150 mg) once daily in period 2 (days 8–14). Blood samples were collected before and after dosing. A PBPK model (PK-SIM® version 11.2, Open Systems Pharmacology, USA) of ainuovirine and fluconazole was developed and validated to predict their DDIs.

Results: All subjects (N = 36) completed the study. In group A, when co-administered with fluconazole, geometric means of ainuovirine pharmacokinetics parameters C_min,ss, AUC_0–24,ss increased up to 233.0% and 349.6%, respectively, vs. ainuovirine alone, whereas the median T_max,ss was unaffected. In group B, there were no apparent effects of ainuovirine on C_max,ss, AUC_0–24,ss and T_max,ss for fluconazole. Possible treatment-related adverse events (AEs) assessed by investigators were fewer in group A (83.3%) vs. group B (94.4%), no death or grade ≥3 serious AE was reported. The PBPK modelling supports a dose reduction by half for co-administration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.

Conclusion: Co-administration of ainuovirine with fluconazole significantly increased ainuovirine systemic exposure, whereas ainuovirine did not appear to affect the exposure of fluconazole. The PBPK modelling supports a dose reduction by half (i.e. 75 mg) for coadministration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.

Keywords: ainuovirine, CPY2C19, drug–drug interactions, fluconazole, pharmacokinetics