PMID- 35485346 OWN - NLM STAT- MEDLINE DCOM- 20220502 LR - 20220607 IS - 2040-2058 (Electronic) IS - 1359-6535 (Linking) VI - 26 IP - 1-2 DP - 2021 Jan-Feb TI - Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers. PG - 13-24 LID - 10.1177/13596535211044331 [doi] AB - BACKGROUND: Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. METHODS: This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults (n = 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. RESULTS: Less than dose-proportional increases in maximum plasma concentrations (C(max)) 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(max) and AUC were approximately 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 in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. CONCLUSIONS: 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. FAU - Kakuda, Thomas N AU - Kakuda TN AUID- ORCID: 0000-0001-6857-2572 AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Yogaratnam, Jeysen Z AU - Yogaratnam JZ AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Westland, Christopher AU - Westland C AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Gane, Edward J AU - Gane EJ AD - New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand. FAU - Schwabe, Christian AU - Schwabe C AD - Auckland Clinical Studies, Auckland, New Zealand. FAU - Vuong, Jennifer AU - Vuong J AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Patel, Megha AU - Patel M AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Snoeys, Jan AU - Snoeys J AD - 50148Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Talloen, Willem AU - Talloen W AD - 50148Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Lenz, Oliver AU - Lenz O AD - 50148Janssen Pharmaceutica NV, Beerse, Belgium. FAU - Fry, John AU - Fry J AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - Chanda, Sushmita AU - Chanda S AD - 333755Janssen BioPharma Inc., South San Francisco, CA, USA. FAU - van Remoortere, Pieter AU - van Remoortere P AUID- ORCID: 0000-0002-5537-5008 AD - Janssen Pharmaceuticals, Titusville, NJ, USA. LA - eng SI - ClinicalTrials.gov/NCT03439488 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210923 PL - England TA - Antivir Ther JT - Antiviral therapy JID - 9815705 RN - 0 (Antiviral Agents) SB - IM MH - Adult MH - Antiviral Agents/pharmacokinetics MH - Area Under Curve MH - *Capsid MH - Healthy Volunteers MH - *Hepatitis B virus MH - Humans OTO - NOTNLM OT - JNJ-64530440 OT - capsid assembly modulator OT - chronic hepatitis B OT - pharmacokinetics OT - safety EDAT- 2021/01/01 00:00 MHDA- 2022/05/03 06:00 CRDT- 2022/04/29 05:53 PHST- 2022/04/29 05:53 [entrez] PHST- 2021/01/01 00:00 [pubmed] PHST- 2022/05/03 06:00 [medline] AID - 10.1177/13596535211044331 [doi] PST - ppublish SO - Antivir Ther. 2021 Jan-Feb;26(1-2):13-24. doi: 10.1177/13596535211044331. Epub 2021 Sep 23.