Kakuda Thomas N, Yogaratnam Jeysen Z, Westland Christopher, Gane Edward J, Schwabe Christian, Vuong Jennifer, Patel Megha, Snoeys Jan, Talloen Willem, Lenz Oliver, Fry John, Chanda Sushmita, van Remoortere Pieter
333755Janssen BioPharma Inc., South San Francisco, CA, USA.
New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand.
Antivir Ther. 2021 Jan-Feb;26(1-2):13-24. doi: 10.1177/13596535211044331. Epub 2021 Sep 23.
Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated.
This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults ( = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout.
Less than dose-proportional increases in maximum plasma concentrations (C) and area under the plasma concentration-time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. C and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose.
Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.
评估了乙肝病毒衣壳组装调节剂JNJ-64530440（一种产生正常空衣壳的调节剂，简称CAM-N）在健康志愿者中的药代动力学和安全性。
这项I期研究（NCT03439488）是一项双盲、随机、安慰剂对照研究。成年人（每组n = 10，5名亚洲人/5名非亚洲人），随机分为4:1，在禁食（50、150、300和900毫克）或进食（300、750、1000、2000和4000毫克）条件下接受单剂量递增的口服JNJ-64530440（第一代和第二代制剂）或安慰剂。评估了每天一次750或2000毫克以及每天两次750毫克JNJ-64530440（第二代制剂）连续7天的多剂量递增情况。根据血浆浓度估算药代动力学参数。全程评估安全性。
各剂量下均观察到最大血浆浓度（Cmax）和血浆浓度-时间曲线下面积（AUC）的增加低于剂量比例。平均血浆半衰期为9.3至14.5小时。进食条件下的Cmax和AUC比禁食条件下高约两倍，亚洲人的数值略高于白种人。JNJ-64530440剂量≥750毫克时达到的血浆水平高于蛋白结合调整浓度，显示出抗病毒活性。未观察到严重不良事件（AE）、治疗中断或剂量限制性毒性。AE的频率/严重程度未随剂量增加。
JNJ-64530440的单剂量（最高4000毫克）和多剂量（最高2000毫克，持续7天）在健康志愿者中耐受性良好。每天多剂量≥750毫克可达到预期具有抗病毒活性的血浆浓度，可能降低乙肝表面抗原。亚洲人和白种人在耐受性或药代动力学参数方面未观察到临床相关差异。
