Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies

Abstract

22

Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies

Su Bin¹, Wu Hao¹, Wang Meixia¹, Hao Xiaohua², Hong Qin³ and Wu Yuechan³

¹Beijing Youan Hospital Affiliated to Capital Medical University; ²Beijing Ditan Hospital Affiliated to Capital Medical University; ³Jiangsu Aidea Pharmaceutical Co., Ltd

Background: People with HIV-1 (PWH) are susceptible to corrected QT (QTc) interval prolongation, especially when on some specific antiretroviral regimens. Ainuovirine (ANV) is a new-generation NNRTI developed for HIV-1 treatment. The pooled analyses aimed to investigate effects of ainuovirine monotherapy and combined with lamivudine (3TC) and tenofovir DF (TDF) on electrocardiography and myocardial biomarker of healthy people and treatment-naïve PWH.

Methods: Sixty-eight (n = 68) healthy adults were enrolled and exposed to ANV in single ascending dose (SAD), food effect (FE) and drug–drug interaction (DDI) with 3TC/TDF studies; 28 PWH were enrolled into multiple ascending dose (MAD) study and received ANV monotherapy for 10 successive days. ANV, 75–300 mg, was given to all participants under the fasting condition. A basic structure model (c-QTc) was established between observed plasma ANV concentration and change in corrected QT interval (ΔQTcF) with the linear mixed effect method. All model parameters were estimated using the first-order conditional estimation with interaction (FOCEI), with the linear model prioritized. An additional statistical random effect model was used to depict inter- and intra-individual variations without covariate adjusted. A simple linear regression model was also used to evaluate the correlation between ΔQTcF and plasma concentration, regardless of inter-individual variability. A 95% confidence interval containing 0 for the slope indicates negative QT prolongation. Changes in concentration-creatine kinase MB (c-CKMB) were also analysed using a similar methodology for evaluation of ANV myocardial safety.

Results: A total of 492 post-dose ECG sampling points from 85 participants were included in the analysis. A linear population c-QTc model was established, which demonstrated the 95% CI of [−0.018, 0.0064] for the slope (containing 0), with favourable goodness of fit, precision and reliability. The simple linear regression model showed a slope of −0.003 [−0.010, 0.004], with no statistically significant difference from 0 (p = .409). CKMB levels did not change significantly with ACC007 monotherapy and remained well below the upper limit of normal (ULN, 3.6 ng/mL); CKMB levels were significantly higher and beyond the ULN (25 U/L) in 16/23 participants on ANV plus 3TC/TDF. Elevations in CKMB was not associated with exposure of ANV or 3TC but with that of TDF in PWH on combined therapy.

Conclusions: ANV monotherapy had no significant effect on QTc prolongation, at a dose range of 75–300 mg, in both healthy adults and PWH. No significant association was found between change in CKMB and ANV exposure. Exposure to co-administered TDF might contribute to increase in CKMB but required no dose adjustment based on systemic exposure bioequivalence.

Key words: ainuovirine; corrected QT interval; creatine kinase MB; exposure–response model; people with HIV