PMID- 34585528 OWN - NLM STAT- MEDLINE DCOM- 20220404 LR - 20220405 IS - 2163-8306 (Electronic) IS - 2163-8306 (Linking) VI - 10 IP - 11 DP - 2021 Nov TI - Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor. PG - 1422-1432 LID - 10.1002/psp4.12712 [doi] AB - This analysis was conducted to assess exposure-response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (C(avg) ) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher C(avg) coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between C(avg) and incidence of ALT-related and AST-related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT-related and AST-related AEs. These results support the US Food and Drug Administration-approved dose (400 mg two times/day without initial loading dose). CI - (c) 2021 Daiichi Sankyo, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Yin, Ophelia AU - Yin O AD - Quantitative Clinical Pharmacology and Translational Sciences, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA. FAU - Zahir, Hamim AU - Zahir H AD - Quantitative Clinical Pharmacology and Translational Sciences, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA. FAU - French, Jonathan AU - French J AD - Metrum Research Group, Tariffville, Connecticut, USA. FAU - Polhamus, Daniel AU - Polhamus D AD - Metrum Research Group, Tariffville, Connecticut, USA. FAU - Wang, Xiaoning AU - Wang X AD - Metrum Research Group, Tariffville, Connecticut, USA. FAU - van de Sande, Michiel AU - van de Sande M AD - Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands. FAU - Tap, William D AU - Tap WD AD - Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Gelderblom, Hans AU - Gelderblom H AD - Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. FAU - Wagner, Andrew J AU - Wagner AJ AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Healey, John H AU - Healey JH AD - Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Greenberg, Jonathan AU - Greenberg J AD - Global Oncology R&D, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA. FAU - Shuster, Dale AU - Shuster D AD - Global Oncology R&D, Daiichi Sankyo, Inc., Basking Ridge, New Jersey, USA. FAU - Stacchiotti, Silvia AU - Stacchiotti S AD - Department of Medical Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - Daiichi Sankyo, Inc./ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211014 PL - United States TA - CPT Pharmacometrics Syst Pharmacol JT - CPT: pharmacometrics & systems pharmacology JID - 101580011 RN - 0 (Aminopyridines) RN - 0 (Pyrroles) RN - 6783M2LV5X (pexidartinib) SB - IM MH - Aminopyridines MH - *Giant Cell Tumor of Tendon Sheath/drug therapy/pathology MH - Humans MH - *Pyrroles MH - Response Evaluation Criteria in Solid Tumors PMC - PMC8592513 COIS- O.Y. reports employment with Daiichi Sankyo at the time of study. H.Z. reports employment with Daiichi Sankyo. J.F. reports consulting fees to his company from Daiichi Sankyo. D.P. reports consulting fees to his company from Daiichi Sankyo. X.W. reports consulting fees to her company from Daiichi Sankyo. M.v.d.S. reports grants to his institution from Daiichi Sankyo during the conduct of the study. W.D.T. reports a standard budget for site participation in clinical trial from Plexxikon; personal fees for serving on advisory boards and consulting from Agios Pharmaceuticals, Blueprint, C4 Therapeutics, Daiichi Sankyo, Eli Lilly, EMD Serono, GlaxoSmithKline, and Mundipharma outside the submitted work; personal fees for serving on advisory boards of NanoCarrier and Deciphera outside the submitted work; personal fees for consulting from AbMaxBio, Adcendo, Ayala Pharmaceuticals, Kowa, and Servier outside the submitted work; a patent Companion Diagnostic for CDK4 inhibitors-14/854,329 pending to Memorial Sloan Kettering Cancer Center/Sloan Kettering Institute; a patent Enigma and CDH18 as Companion Diagnostics for CKD4 inhibition-SKI2016-021-03 pending to Memorial Sloan Kettering Cancer Center/Sloan Kettering Institute; participation on the scientific advisory boards for Certis Oncology Solutions and Innova Therapeutics; stock ownership in Certis Oncology Solutions and Atropos Therapeutics; and is cofounder of Atropos Therapeutics. H.G. reports research compensation to his institution (Leiden University Medical Center) from Daiichi Sankyo. A.J.W. reports grants for research from Aadi Bioscience, Daiichi Sankyo, Deciphera, Eli Lilly, Karyopharma, and Plexxikon outside the submitted work and served on advisory boards for Daiichi Sankyo, Deciphera, Eli Lilly, and Mundipharma outside the submitted work. J.H.H. reports personal fees for consulting from Daiichi Sankyo outside the submitted work. J.G. reports employment with Daiichi Sankyo. D.S. reports employment with and stock ownership in Daiichi Sankyo during the conduct of the study and outside the submitted work and stock ownership in Amgen, Bristol Myers Squibb, Exelixis, Merck, Pfizer, and Regeneron outside the submitted work. S.S. reports personal fees for consulting from Bayer, Bavarian Nordic, Deciphera, Eli Lilly, Epizyme Inc, Daiichi Sankyo, Karyopharm, Immune Design, Intellisphere, Maxivax, PharmaMar, and Takeda outside the submitted work; research funding to her institution from Amgen Dompe, Advenchen, Bayer, Bavarian Nordic, Blueprint, Deciphera, Eli Lilly, Epizyme Inc, Daiichi Sankyo, Karyopharm, Novartis, Pfizer, and PharmaMar outside the submitted work; travel coverage from PharmaMar outside the submitted work; and honoraria from Eli Lilly and PharmaMar outside the submitted work. No other conflicts of interest were reported. As an Associate Editor of CPT: Pharmacometrics & Systems Pharmacology, Jonathan French was not involved in the review or decision process for this article. EDAT- 2021/09/30 06:00 MHDA- 2022/04/05 06:00 PMCR- 2021/11/01 CRDT- 2021/09/29 07:20 PHST- 2021/08/30 00:00 [revised] PHST- 2021/06/14 00:00 [received] PHST- 2021/09/01 00:00 [accepted] PHST- 2021/09/30 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2021/09/29 07:20 [entrez] PHST- 2021/11/01 00:00 [pmc-release] AID - PSP412712 [pii] AID - 10.1002/psp4.12712 [doi] PST - ppublish SO - CPT Pharmacometrics Syst Pharmacol. 2021 Nov;10(11):1422-1432. doi: 10.1002/psp4.12712. Epub 2021 Oct 14.