Drug‐Drug Interactions With the Hepatitis B Virus Capsid Assembly Modulator JNJ‐56136379 (Bersacapavir)

Abstract

The capsid assembly modulator JNJ‐56136379 (bersacapavir) disrupts hepatitis B virus replication. It is metabolized via cytochrome P450 (CYP) 3A, but little is known about the drug‐drug interactions of JNJ‐56136379 when combined with drugs that inhibit or are metabolized by CYP3A. In a phase 1, open‐label trial (NCT03945539), healthy adults received 1 dose of JNJ‐56136379 with and without 21 days of prior exposure to itraconazole 200 mg (CYP3A inhibitor). In a second phase 1, open‐label trial (NCT03111511), healthy women received 1 dose of drospirenone/ethinyl estradiol and midazolam before and after 15 days of JNJ‐56136379. Itraconazole increased the area under the plasma concentration–time curve (AUC) of JNJ‐56136379 by 38%. JNJ‐56136379 reduced the maximum observed concentration and AUC of midazolam (CYP3A substrate) by 42%–54%, increased AUC of ethinyl estradiol by 1.6‐fold, but had no effect on drospirenone pharmacokinetics. Overall, these results demonstrated that a strong CYP3A inhibitor (itraconazole) modestly increased JNJ‐56136379 exposure. Furthermore, JNJ‐56136379 was a weak inducer of CYP3A (midazolam) and increased ethinyl estradiol exposure; coadministration of high‐dose estrogen‐based contraceptives and JNJ‐56136379 is not recommended.

Pharmacokinetics of JNJ‐73763989 and JNJ‐56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment

“…For JNJ‐56136379, blood samples were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 120, 216, 312, and 480 hours post dose, with analyses for JNJ‐56136379 plasma concentrations performed using liquid chromatography tandem mass spectrometry with an LLOQ of 10.0 ng/mL (PRA, Assen, the Netherlands). Details of the method are published elsewhere 19 . For plasma protein binding, the optimal test conditions, including time, temperature, pH, stability, and recovery, were tested previously in a separate in vitro study.…”

“…Details of the method are published elsewhere. 19 For plasma protein binding, the optimal test conditions, including time, temperature, pH, stability, and recovery, were tested previously in a separate in vitro study. Plasma protein binding of JNJ-56136379 was determined in venous blood samples taken predose and at 4 hours post dose on day 1.…”

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

“… 3 , 5 The administration of itraconazole pre‐exposure in DDI studies is also different in recent practice, varying from 200 mg QD for 3–5 days with or without a loading dose. 6 , 7 , 8 Discrepancies in current studies might influence the accuracy and objectivity of clinical DDIs. In addition, most studies using simulation and exploration of improved methods have been very limited.…”