Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Beijing BioVoice Technology Co., Ltd., Beijing 100068, China.
Chin Med J (Engl). 2024 Oct 20;137(20):2473-2482. doi: 10.1097/CM9.0000000000002917. Epub 2024 Jun 27.
Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.
Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.
ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively).
Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.
Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).
Ainuovirine (ANV) 是一种新型非核苷类逆转录酶抑制剂，用于治疗人类免疫缺陷病毒 (HIV) 1 型感染。本研究旨在评估 HIV 感染者中 ANV 的群体药代动力学 (PopPK) 特征和暴露-反应关系。
将 ANV 的 1 期和 3 期临床试验的血浆浓度-时间数据进行汇总，以建立 PopPK 模型。使用最终模型获得的暴露估计值进行暴露-反应分析，以评估病毒学反应和安全性反应。
ANV 表现出非线性药代动力学特征，最佳描述为具有一级消除的两室模型。未发现与 ANV 药代动力学参数相关的显著协变量。经生物利用度校正的清除率（CL/F）的 PopPK 参数估计值（相对标准误差 [%]）为 6.46（15.00）L/h，且 ANV 的清除率在多次给药后增加。暴露-反应模型显示，48 周时病毒学反应（HIV-RNA<50 拷贝/mL）与暴露之间无显著相关性，但不良反应发生率随暴露增加而增加（稳态谷浓度和稳态曲线下面积的 P 值分别为 0.0177 和 0.0141）。
我们的 PopPK 模型支持将 ANV 150mg 每日一次作为 HIV 感染者的推荐剂量，无需针对研究因素进行剂量调整。由于不良反应随暴露增加呈上升趋势，在临床实践中可能需要优化 ANV 剂量。
中国临床试验注册中心 https://www.chictr.org.cn（注册号 ChiCTR1800018022 和 ChiCTR1800019041）。
