PMID- 38105420 OWN - NLM STAT- MEDLINE DCOM- 20240125 LR - 20240417 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 17 IP - 1 DP - 2024 Jan TI - No drug-drug interactions between selective prolyl-tRNA synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants. PG - e13701 LID - 10.1111/cts.13701 [doi] LID - e13701 AB - Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty-six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib. CI - (c) 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Shin, Wonsuk AU - Shin W AUID- ORCID: 0000-0002-6163-5726 AD - Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - CHA Global Clinical Trial Center, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Republic of Korea. FAU - Park, Min Young AU - Park MY AD - Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. FAU - Kim, Jongwoo AU - Kim J AD - Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. FAU - Kim, Jihyeon AU - Kim J AD - Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. FAU - Nam, Jun Hee AU - Nam JH AD - Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. FAU - Choi, Jongwon AU - Choi J AD - Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea. FAU - Yang, A-Young AU - Yang AY AUID- ORCID: 0000-0002-2960-580X AD - Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - CHA Global Clinical Trial Center, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Republic of Korea. FAU - Yoo, Hyounggyoon AU - Yoo H AUID- ORCID: 0000-0003-2785-4383 AD - Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - CHA Global Clinical Trial Center, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Republic of Korea. FAU - Lee, Yil-Seob AU - Lee YS AUID- ORCID: 0000-0002-4597-5990 AD - Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - CHA Global Clinical Trial Center, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Republic of Korea. FAU - Kim, Anhye AU - Kim A AUID- ORCID: 0000-0002-6622-8089 AD - Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - CHA Global Clinical Trial Center, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Republic of Korea. AD - Institute for Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - G6HRD2P839 (nintedanib) RN - D7NLD2JX7U (pirfenidone) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - 0 (Pyridones) RN - 0 (Tablets) RN - 0 (Indoles) SB - IM MH - Humans MH - Healthy Volunteers MH - *Cytochrome P-450 CYP2D6 MH - Treatment Outcome MH - *Idiopathic Pulmonary Fibrosis/chemically induced/drug therapy MH - Pyridones MH - Drug Interactions MH - Tablets/therapeutic use MH - *Indoles PMC - PMC10777433 COIS- This study was sponsored by Daewoong Pharmaceutical Co., Ltd, Seoul, Republic of Korea. M.Y.P., Jo.K., Ji.K., J.H.N., and J.C. are employees of Daewoong Pharmaceutical. All the other authors report no conflicts of interest associated with this work. EDAT- 2023/12/18 00:42 MHDA- 2024/01/25 06:44 PMCR- 2024/01/01 CRDT- 2023/12/17 23:53 PHST- 2023/11/23 00:00 [revised] PHST- 2023/06/27 00:00 [received] PHST- 2023/11/28 00:00 [accepted] PHST- 2024/01/25 06:44 [medline] PHST- 2023/12/18 00:42 [pubmed] PHST- 2023/12/17 23:53 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - CTS13701 [pii] AID - 10.1111/cts.13701 [doi] PST - ppublish SO - Clin Transl Sci. 2024 Jan;17(1):e13701. doi: 10.1111/cts.13701.