An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 mg [ 14 C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 mg dose followed by an oral 800 mg dose of [ 14 C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (F abs), proportion of nemiralisib escaping gut wall metabolism (F g), hepatic extraction (E h), fraction of dose absorbed from inhaled dose (F lung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while F lung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (F abs , 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (F g and E h being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14 C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (F abs), the proportion of drug escaping first-pass extraction through the gut wall and liver (F g and F h) and hepatic extraction (E h). Entero-test bile sampling enabled characterization of biliary elimination pathways.

Max word count; current word count: 4000; 3988No. tables/figures: 5 (3 tables, 2 figures) Principal Investigator statementThe authors confirm that the PI for this paper is Dave Singh and that he had direct clinical responsibility for patients. Data availability statementAnonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. The trial protocol is available at https://www.gsk-studyregister.com/en/ Funding sources and roleThis study was funded by GlaxoSmithKline (GSK ID 205722; NCT03287310) Authors contributionsAll authors reviewed and revised the manuscript, approved the final version, and made the decision to submit the manuscript for publication. Additionally, SM, IJP and NPB were involved in the conception and design of the study, DS and RF were involved in the acquisition of the data, and IJP, KH, YLM, NPB, SWY and AC were involved in the data analysis and interpretation.