Advances in therapy · 2019
Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Vandenbossche Joris, Jessner Wolfgang, van den Boer Maarten, Biewenga Jeike, Berke Jan Martin, Talloen Willem, De Zwart Loeckie, Snoeys Jan, Yogaratnam Jeysen
Аннотация
INTRODUCTION: Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses.
METHODS: This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days.
RESULTS: The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE.
CONCLUSION: JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro.
TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02662712.
FUNDING: Janssen Pharmaceutica.
METHODS: This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days.
RESULTS: The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE.
CONCLUSION: JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro.
TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02662712.
FUNDING: Janssen Pharmaceutica.