Exposure–Response Modeling of QTc Interval and Creatine Kinase-MB in Healthy People and Treatment-Naïve Adults Living with HIV-1 Treated with Ainuovirine Monotherapy or Combined with Lamivudine and Tenofovir DF

BACKGROUND: Corrected QT (QTc) interval prolongation elevates fatal arrhythmia risk in people living with HIV (PLWH). Ainuovirine (ANV), a novel non-nucleoside reverse transcriptase inhibitor, demonstrates a favorable preclinical safety profile. This study evaluated ANV's effects on QTc interval and creatine kinase MB (CK-MB) levels in humans. METHODS: A pooled analysis was conducted using data from four phase 1 clinical studies: a single ascending dose (SAD), a food effect (FED), a multiple ascending dose (MAD), and a drug-drug interaction (DDI) study with lamivudine/tenofovir disoproxil fumarate (3TC/TDF). The analysis included healthy adults and treatment-naïve PLWH receiving ANV monotherapy or combination therapy. Concentration-QTc (C-QTc) modeling was performed using linear regression and linear mixed-effects (LME) models. The relationship between drug exposure (ANV, 3TC, TDF) and serum CK-MB levels was also assessed. RESULTS: Analysis of 85 participants with 838 time-matched C-QTc pairs revealed statistically insignificant negative slopes for ANV C-QTc relationships across all models. This indicates no significant ANV effect on QTc prolongation, consistent from subtherapeutic to supratherapeutic doses (75-300 mg). Bootstrapping validated model precision and reliability. ANV and lamivudine exposures showed no correlation with CK-MB elevation, while tenofovir disoproxil fumarate exposure demonstrated a positive correlation that remained clinically insignificant. CONCLUSIONS: ANV exhibits no statistically significant or clinically meaningful effect on QTc interval prolongation in healthy adults and treatment-naïve PLWH, even at supratherapeutic doses. CK-MB elevations were associated with tenofovir disoproxil fumarate exposure rather than ANV or lamivudine. These findings support the favorable cardiac safety profile of ANV-based regimens.