Program

PO1-11-17

Safety, tolerability and pharmacokinetics of a novel oral hepatitis C virus NS5A inhibitor DAG181PA Capsules in Chinese healthy volunteers

[Speaker] Ran Xie:1
[Co-author] Xia Zhao:1, Nan Zhao:1, Lin Luo:2, Zhangma Huang:2, Hongming Xie:2, Yingjun Zhang:2, Junyu Xu:1, Yimin Cui:1
1:Department of Pharmacy, Peking University First Hospital, China, 2:Sunshine Lake Pharma Co. Ltd, China

Background: NS5A protein plays a key role in HCV replication. DAG181PA, an inhibitor of NS5A protein, preclinical data showed that it has favorable in vitro and in vivo properties. Our aim is to evaluate the tolerability, safety and pharmacokinetics of DAG181PA in healthy volunteers. Methods: A randomized, double-blind, placebo-controlled, single-ascending dose (30,100,200 and 400mg) and multiple-ascending dose (100mg and 200mg once daily for 7 days) study was performed in 32 and 24 healthy subjects respectively. An additional group of 15 subjects received an open-label dose of DAG181PA 100mg in the fasted condition and after a meal. Pharmacokinetic assessments included plasma, urine and faecal samples. Results: All doses of DAG181PA were well tolerated both as single oral doses or once oral doses for 7 days. All the AEs were mild except one subject with moderate urticaria in the placebo group, resolving with symptomatic treatment. After administration a single dose of DAG181PA 30 to 100 mg, DAG181PA values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax), while increased slowly from 100mg to 400mg. Approximately 64.8 to 76.1% of the doses were excreted in feces. Steady state was reached by day 7 of dosing with minimal accumulation of DAG181PA. Administration of DAG181PA with food delayed its absorption and reduced its exposure relative to the fasted state, with a median Tmax 4.0 to 10.0h, mean Cmax 519 to 189 ng/mL and mean AUC0-t 7800 to 3970h*ng/mL in fasting and fed conditions. Conclusion: DAG181PA was considered safe and well tolerated in healthy subjects. Less than dose-proportional increases in its exposure after single oral administration of DAG181PA 100 to 400 mg, which primarily excreted in feces. Minimal accumulation was predicted and observed for DAG181PA. The extent of absorption was significantly affected by food.

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