Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: After multiple-dose administration of HS-10234 with emtricitabine, the AUC(0-tau) of HS-10234 and TFV-DP was 1.327- and 1.403-fold higher than that with HS-10234 administration alone. The C(max) and AUC(0-tau) 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. CONCLUSIONS: 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. TRIAL REGISTRATION: NCT04477096, July 20, 2020.