Integrating Duodenal Sampling in a Human Mass Balance Study to Quantify the Elimination Pathways of JNJ-53718678, a Respiratory Syncytial Virus Fusion Protein Inhibitor
Advances in Therapy(2019)
摘要
Introduction The study objective was to characterize the excretion and metabolic profile of the respiratory syncytial virus fusion protein inhibitor, JNJ-53718678. Prior animal and in vitro studies suggested three main elimination pathways: N-glucuronidation to M8; CYP(3A4) metabolism leading to circulating metabolites M5, M12, M19 and M37; and JNJ-53718678 biliary excretion. To gain insight into the relative contribution of JNJ-53718678 and M8 biliary excretion, duodenal fluid sampling was incorporated into this mass balance study. Methods A single oral dose of 500 mg 14 C-JNJ-53718678 was administered to six healthy male subjects. Four hours after study drug intake, gallbladder contraction was stimulated and duodenal fluid samples were collected. JNJ-53718678, its key circulating metabolites and total radioactivity (TR) were quantified in plasma, feces, urine and duodenal fluid. Safety was monitored throughout. Results JNJ-53718678 and M12 represented 47.4% and 17.8%, respectively, of TR area under the curve (AUC) ∞ in plasma. M37 (9.6%), M19 (5.2%), M5 (4.3%) and M8 (1.4%) were minor metabolites; 70.6% of TR was recovered in feces and 19.9% in urine. Duodenal fluid concentrations (% of TR) were highest for JNJ-53718678 (11.6%) followed by M8 (10.4%), M5 (5.9%) and M12 (1.1%). In feces, 10–16% of TR was JNJ-53718678, 5–8% M5, < 1% M12 and < 1% M8. N-glucuronidation to M8 and direct biliary excretion of JNJ-53718678 represented 7% and 8% of drug clearance, respectively. JNJ-53718678 was safe and well tolerated. Conclusions JNJ-53718678 is primarily eliminated through CYP3A4-mediated metabolism. By integrating duodenal sampling, N-glucuronidation was confirmed as another metabolic pathway despite the low amount of M8 excreted in urine and feces. Trial Registration Eudract no. 2016-002664-14.
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关键词
Duodenal fluid sampling,Infectious disease,JNJ-53718678,Mass balance,Respiratory syncytial virus
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