Population Pharmacokinetics of <scp>siRNA JNJ</scp> ‐73763989 in Healthy Participants and Patients With Chronic Hepatitis B

JNJ-73763989 is a combination product consisting of two N-acetylgalactosamine-conjugated short-interfering RNA triggers (JNJ-73763976 and JNJ-73763924) that are in development as a potential treatment for chronic hepatitis B virus infection. A population pharmacokinetic model for JNJ-73763989 was developed based on pooled data from seven clinical studies to characterize the plasma pharmacokinetics of the short-interfering RNAs following subcutaneous administration. Additionally, simulations of liver (target organ) exposure using the final population pharmacokinetic model in conjunction with preclinical information were performed. Disposition of JNJ-73763976 and JNJ-73763924 was governed by a linear two-compartment model describing the peripheral distribution of both short-interfering RNAs and a saturable component describing liver uptake via the asialoglycoprotein receptor. While the estimated first-order absorption rate constant was similar for both short-interfering RNAs, the corresponding absorption half-life values were 20- to 40-fold longer than the estimated plasma elimination half-life for both short-interfering RNAs, indicating absorption rate-limited or "flip-flop" kinetics. Plasma-to-liver transport of each short-interfering RNA was modeled by a saturable, receptor-mediated competitive process, and the affinity for the asialoglycoprotein receptor was 2.5-fold higher for JNJ-73763924 relative to JNJ-73763976. Predicted liver concentrations of both short-interfering RNA triggers approached steady state after 12 months of JNJ-73763989 treatment. The 2:1 dosing ratio of JNJ-73763976 to JNJ-73763924 was predicted to maintain an ~2:1 liver concentration ratio, irrespective of the identified plasma disposition differences between the triggers. Body weight, creatinine clearance, presence of chronic hepatitis B, and hepatic impairment were associated with plasma pharmacokinetic parameters and were included in the final population pharmacokinetic model.