Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor Journal Article
| Authors: | Yin, O.; Zahir, H.; French, J.; Polhamus, D.; Wang, X.; van de Sande, M.; Tap, W. D.; Gelderblom, H.; Wagner, A. J.; Healey, J. H.; Greenberg, J.; Shuster, D.; Stacchiotti, S. |
| Article Title: | Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor |
| Abstract: | 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 (Cavg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg 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 Cavg 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). © 2021 Daiichi Sankyo, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics |
| Keywords: | adult; controlled study; middle aged; major clinical study; drug efficacy; drug safety; nuclear magnetic resonance imaging; tumor volume; food and drug administration; open study; phase 3 clinical trial; phase 1 clinical trial; drug dose increase; double blind procedure; overall response rate; human; female; article; pexidartinib; giant cell tumor of tendon sheath; pharmacodynamic parameters |
| Journal Title: | CPT: Pharmacometrics and Systems Pharmacology |
| Volume: | 10 |
| Issue: | 11 |
| ISSN: | 2163-8306 |
| Publisher: | John Wiley & Sons, Inc. |
| Date Published: | 2021-11-01 |
| Start Page: | 1422 |
| End Page: | 1432 |
| Language: | English |
| DOI: | 10.1002/psp4.12712 |
| PUBMED: | 34585528 |
| PROVIDER: | scopus |
| PMCID: | PMC8592513 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2021 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work