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

Eur J Pharm Sci. 2026 Jul 1:222:107544. doi: 10.1016/j.ejps.2026.107544. Epub 2026 May 3.

Abstract

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.

Keywords: Ainuovirine; Cardiac safety; Creatine kinase MB; Drug-drug interaction; QT prolongation; concentration-QTc modeling.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Anti-HIV Agents* / administration & dosage
  • Anti-HIV Agents* / adverse effects
  • Anti-HIV Agents* / pharmacokinetics
  • Creatine Kinase, MB Form* / blood
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Therapy, Combination
  • Electrocardiography / drug effects
  • Female
  • HIV Infections* / blood
  • HIV Infections* / drug therapy
  • HIV-1
  • Humans
  • Lamivudine* / administration & dosage
  • Lamivudine* / adverse effects
  • Lamivudine* / pharmacokinetics
  • Lamivudine* / therapeutic use
  • Male
  • Middle Aged
  • Reverse Transcriptase Inhibitors* / administration & dosage
  • Reverse Transcriptase Inhibitors* / adverse effects
  • Tenofovir* / administration & dosage
  • Tenofovir* / adverse effects
  • Tenofovir* / pharmacokinetics
  • Tenofovir* / therapeutic use
  • Young Adult

Substances

  • Tenofovir
  • Lamivudine
  • Anti-HIV Agents
  • Creatine Kinase, MB Form
  • Reverse Transcriptase Inhibitors