First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects

Zhang, Hong; Gao, Lei; Lou, Jinfeng; Wu, Min; Chen, Hong; Yang, Lizhi; Liu, Jingrui; Zhu, Xiaodong; Li, Xiaojiao; Li, Cuiyun; Wang, Meng; Liu, Chengjiao; Guo, Wenlei; Wang, Yuan; Gao, Zhongqiang; Han, Lei; Wang, Daidi; Jin, Weili; Ding, Yanhua

doi:10.3389/fphar.2022.873588

Cited by 3 publications

(1 citation statement)

References 25 publications

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“… 11 Long-term high-dose TDF therapy (300 mg daily) can cause renal and skeletal adverse reactions such as proximal tubular dysfunction, osteomalacia, and hypophosphatemia. 12 In vitro and in vivo studies suggest that ETV can completely inhibit HBV DNA replication. 13 and suppress circulating HBV DNA, but not circulating HBsAg and HBeAg.…”

Section: Introductionmentioning

confidence: 99%

Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression

Liu,

Pang,

Wan

et al. 2024

J Clin Transl Hepatol

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Background and Aims Hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and liver cancer, and its treatment continues to be difficult. We previously demonstrated that a dopamine analog inhibited the packaging of pregenomic RNA into capsids. The present study aimed to determine the effect of dopamine on the expressions of hepatitis B virus surface and e antigens (HBsAg and HBeAg, respectively) and to elucidate the underlying mechanism. Methods We used dopamine-treated HBV-infected HepG2.2.15 and NTCP-G2 cells to monitor HBsAg and HBeAg expression levels. We analyzed interferon-stimulated gene 15 (ISG15) expression in dopamine-treated cells. We knocked down ISG15 and then monitored HBsAg and HBeAg expression levels. We analyzed the expression of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway factors in dopamine-treated cells. We used dopamine hydrochloride-treated adeno-associated virus/HBV-infected mouse model to evaluate HBV DNA, HBsAg, and HBeAg expression. HBV virus was collected from HepAD38.7 cell culture medium. Results Dopamine inhibited HBsAg and HBeAg expression and upregulated ISG15 expression in HepG2.2.15 and HepG2-NTCP cell lines. ISG15 knockdown increased HBsAg and HBeAg expression in HepG2.2.15 cells. Dopamine-treated cells activated the JAK/STAT pathway, which upregulated ISG15 expression. In the adeno-associated virus-HBV murine infection model, dopamine downregulated HBsAg and HBeAg expression and activated the JAK-STAT/ISG15 axis. Conclusions Dopamine inhibits the expression of HBsAg and HBeAg by activating the JAK/STAT pathway and upregulating ISG15 expression.

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Section: Introductionmentioning

confidence: 99%

Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression

Liu,

Pang,

Wan

et al. 2024

J Clin Transl Hepatol

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Liver-targeted delivery based on prodrug: passive and active approaches

Chen,

Yao,

Mao

et al. 2024

Journal of Drug Targeting

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Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171

Zhang,

Zhou,

Chen

et al. 2024

Antimicrob Agents Chemother

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This study is aimed to evaluate the safety, tolerability, and pharmacokinetics (PK), as well as to select an appropriate dosing regimen for the pivotal clinical trial of GST-HG171, an orally bioavailable, potent, and selective 3CL protease inhibitor by a randomized, double-blind, and placebo-controlled phase I trial in healthy subjects. We conducted a Ph1 study involving 78 healthy subjects to assess the safety, tolerability, and PK of single ascending doses (150–900 mg) as well as multiple ascending doses (MADs) (150 and 300 mg) of GST-HG171. Additionally, we examined the food effect and drug–drug interaction of GST-HG171 in combination with ritonavir through a MAD regimen of GST-HG171/ritonavir (BID or TID) for 5 days. Throughout the course of these studies, no serious AEs or deaths occurred, and no AEs necessitated study discontinuation. We observed that food had no significant impact on the exposure of GST-HG171. However, the presence of ritonavir substantially increased the exposure of GST-HG171, which facilitated the selection of the GST-HG171/ritonavir dose and regimen (150/100 mg BID) for subsequent phase II/III trials. The selected dose regimen was achieved through concentrations continuously at 6.2–9.9-fold above the levels required for protein-binding adjusted 50% inhibition (IC50) of viral replication in vitro . The combination of 150 mg GST-HG171/100 mg ritonavir demonstrated favorable safety and tolerability profiles. The PK data obtained from GST-HG171/ritonavir administration guided the selection of appropriate dose for a pivotal phase II/III trial currently in progress. (This study has been registered at ClinicalTrials.gov under identifier NCT05668897).

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First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects

Cited by 3 publications

References 25 publications

Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression

Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression

Liver-targeted delivery based on prodrug: passive and active approaches

Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171

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