Luo Yeping, Chen Wenjing, Yang Guoping, Zou Chan, Huang Jie, Kuang Yun, Shen Kai, Zhang Basheng, Yang Shuang, Xiang Hong, Li Zhuo, Pei Qi
Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Pharmacy, the Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Infect Dis Ther. 2022 Feb;11(1):175-186. doi: 10.1007/s40121-021-00555-y. Epub 2021 Oct 30.
HS-10234, a novel prodrug of tenofovir (TFV), functions by inhibiting nucleotide reverse transcriptase against retroviral infections including hepatitis B virus and human immunodeficiency virus (HIV). As it is a possible substitute for TFV co-administration with emtricitabine, determining the drug-drug interactions (DDI) between HS-10234 and emtricitabine therapy will be helpful for researchers to design and conduct future phase II/III studies and merits careful examination in the era of evolving new combination antiretroviral therapy regimens.
We conducted an open-label, two-sequence, two-period, self-controlled phase I trial that enrolled 36 healthy volunteers randomized into two groups (group 1 and group 2). Eighteen subjects in group 1 were orally administered HS-10234 at a 25-mg daily dose for 7 days during period 1 (D1-D7) followed by co-administration of emtricitabine at a 200-mg dose once daily (QD) for 7 additional days during period 2 (D8-D14). Participants in group 2 were orally administered emtricitabine 200 mg QD for 7 days during period 1 (D1-D7) and then co-administered HS-10234 25 mg QD for 7 additional days during period 2 (D8-D14). Pharmacokinetics (PK) of HS-10234 and emtricitabine were characterized when administered alone and in combination. The concentrations of HS-10234 and its metabolites TFV and emtricitabine were determined using high performance liquid chromatography-mass spectrometry (HPLC-MS)/MS. Peripheral blood monocyte cells (PBMCs) were isolated for detection of intracellular concentrations of HS-10234's active metabolite, intracellular tenofovir diphosphate (TFV-DP) pre-dose and 2, 4, 8, 12 and 24 h post-dose on D7 and D14 in group 1. WinNonlin software was used to calculate PK parameters.
After multiple-dose administration of HS-10234 with emtricitabine, the AUC of HS-10234 and TFV-DP was 1.327- and 1.403-fold higher than that with HS-10234 administration alone. The C and AUC were increased 1.120- and 1.077-fold compared to emtricitabine administration alone. Co-administration of HS-10234 with oral emtricitabine was well tolerated. No serious adverse events were observed.
Although a slightly increased steady-state PK exposure of HS-10234 and TFV-DP was observed with co-administration of oral HS-10234 with emtricitabine, these changes were not considered clinically relevant. Thus, dose adjustments are not recommended for HS-10234 combination with emtricitabine.
NCT04477096, July 20, 2020.
HS-10234是替诺福韦（TFV）的一种新型前体药物，其作用机制是抑制核苷酸逆转录酶，用于治疗包括乙型肝炎病毒和人类免疫缺陷病毒（HIV）在内的逆转录病毒感染。由于它可能替代TFV与恩曲他滨联合使用，确定HS-10234与恩曲他滨治疗之间的药物相互作用（DDI）将有助于研究人员设计和开展未来的II/III期研究，并且在不断发展的新抗逆转录病毒联合治疗方案时代值得仔细研究。
我们进行了一项开放标签、两序列、两周期、自身对照的I期试验，招募了36名健康志愿者，随机分为两组（第1组和第2组）。第1组的18名受试者在第1阶段（D1-D7）每天口服25mg HS-10234，持续7天，然后在第2阶段（D8-D14）每天额外联合口服200mg恩曲他滨，持续7天。第2组的参与者在第1阶段（D1-D7）每天口服200mg恩曲他滨，持续7天，然后在第2阶段（D8-D14）每天额外联合口服25mg HS-10234，持续7天。分别对单独给药和联合给药时HS-10234和恩曲他滨的药代动力学（PK）进行了表征。使用高效液相色谱-质谱联用（HPLC-MS）/MS测定HS-10234及其代谢产物TFV和恩曲他滨的浓度。分离外周血单核细胞（PBMC），以检测第1组在D7和D14给药前以及给药后2、4、8、12和24小时HS-10234活性代谢产物细胞内替诺福韦二磷酸（TFV-DP）的细胞内浓度。使用WinNonlin软件计算PK参数。
HS-10234与恩曲他滨多次给药后，HS-10234和TFV-DP的AUC分别比单独给予HS-10234时高1.327倍和1.403倍。与单独给予恩曲他滨相比，Cmax和AUC分别增加了1.120倍和1.077倍。HS-10234与口服恩曲他滨联合给药耐受性良好。未观察到严重不良事件。
尽管口服HS-10234与恩曲他滨联合给药时，HS-10234和TFV-DP的稳态PK暴露略有增加，但这些变化不被认为具有临床相关性。因此，不建议对HS-10234与恩曲他滨联合用药进行剂量调整。
NCT04477096，2020年7月20日。
