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...

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Autores principales:	Ophelia Yin, Hamim Zahir, Jonathan French, Daniel Polhamus, Xiaoning Wang, Michiel van deSande, William D. Tap, Hans Gelderblom, Andrew J. Wagner, John H. Healey, Jonathan Greenberg, Dale Shuster, Silvia Stacchiotti
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/e98d8752c9444f7c9cdac6701994c7d3
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spelling	oai:doaj.org-article:e98d8752c9444f7c9cdac6701994c7d32021-11-15T18:41:54ZExposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor2163-830610.1002/psp4.12712https://doaj.org/article/e98d8752c9444f7c9cdac6701994c7d32021-11-01T00:00:00Zhttps://doi.org/10.1002/psp4.12712https://doaj.org/toc/2163-8306Abstract 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).Ophelia YinHamim ZahirJonathan FrenchDaniel PolhamusXiaoning WangMichiel van deSandeWilliam D. TapHans GelderblomAndrew J. WagnerJohn H. HealeyJonathan GreenbergDale ShusterSilvia StacchiottiWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 11, Pp 1422-1432 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Ophelia Yin Hamim Zahir Jonathan French Daniel Polhamus Xiaoning Wang Michiel van deSande William D. Tap Hans Gelderblom Andrew J. Wagner John H. Healey Jonathan Greenberg Dale Shuster Silvia Stacchiotti Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
description	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).
format	article
author	Ophelia Yin Hamim Zahir Jonathan French Daniel Polhamus Xiaoning Wang Michiel van deSande William D. Tap Hans Gelderblom Andrew J. Wagner John H. Healey Jonathan Greenberg Dale Shuster Silvia Stacchiotti
author_facet	Ophelia Yin Hamim Zahir Jonathan French Daniel Polhamus Xiaoning Wang Michiel van deSande William D. Tap Hans Gelderblom Andrew J. Wagner John H. Healey Jonathan Greenberg Dale Shuster Silvia Stacchiotti
author_sort	Ophelia Yin
title	Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
title_short	Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
title_full	Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
title_fullStr	Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
title_full_unstemmed	Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
title_sort	exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/e98d8752c9444f7c9cdac6701994c7d3
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Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor

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