Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics

Abstract

Pexidartinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase enzymes, with ZAAD-1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib. The objective of the two phase 1, open-label studies was to determine the pharmacokinetics of pexidartinib after a single 200-mg dose in subjects with mild and moderate HI, based on Child-Pugh classification (PL3397-A-U123: 8 mild HI and 8 moderate HI vs 16 matched healthy controls) and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (PL3397-A-U129: 8 moderate HI versus 8 matched healthy controls [NCT04223635]). Based on Child-Pugh classification, exposure to pexidartinib (maximum observed concentration [Cmax ], area under the plasma concentration-time curve up to the last measurable concentration [AUClast ], and extrapolated to infinity [AUCinf ]) was similar in subjects with mild and moderate HI and in respective matched healthy controls, whereas ZAAD-1006a exposure (AUC) was approximately 27% to 28% and 41% to 48% higher in mild and moderate HI, respectively. According to NCI-ODWG criteria, total pexidartinib exposure was 42% to 46% higher in subjects with moderate HI, compared with healthy controls, and total ZAAD-1006a exposure was 70% to 79% higher for subjects with moderate HI, compared with matched healthy controls with normal hepatic function. These findings were used to develop appropriate dose recommendations in patients with hepatic impairment.

Keywords: Child-Pugh; NCI-ODWG; ZAAD-1006A; hepatic impairment (HI); mild HI; moderate HI; pexidartinib; pharmacokinetics; tenosynovial giant cell tumor (TGCT).

Conflict of interest statement

H.Z. reports employment with and support for study‐related travel from Daiichi Sankyo, Inc., during the time of the study. J.C. reports employment with and stock in Daiichi Sankyo, Inc. C.H. reports employment and stock in Daiichi Sankyo, Inc. T.C.M. and K.C.L. have no potential conflicts of interest to disclose. L.‐A.X. reports employment with and stock and stock options in Daiichi Sankyo, Inc. W.D.T. reports consulting fees and honoraria from Kowa Research Institute, Ayala Pharmaceuticals, Inc., Medpacto, Servier, Novo Holdings, MundiBioPharma, AmMax Bio, C4 Therapeutics, Deciphera, Blueprint, Nano Carrier, EMD Serono, Agios, Daiichi Sankyo, GSK, Eli Lilly, Medscape, Agios, Epizyme, Inc. (Nexus Global Group), Bayer, Cogent Biosciences, Amgen, and Aadi Biosciences; patent and royalties or license from Companion Diagnostics for CDK4 inhibitors (14/854,329); participation on Data Safety Monitoring Board or Advisory Board for C4 Therapeutics, Blueprint, GSK, and MundiBioPharma; leadership or fiduciary role with Osteosarcoma Institute (OSI) and Sarcoma Foundation of America (SFA); stock or stock options in Certis Oncology Solutions and Atropos. J.H.H. reports consulting fees from Daiichi Sankyo, Inc., and Stryker, and participation on Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo, Inc. S.S. reports: funding for the present study from Daiichi; grants to her institution from Advenchen, Amgen Dompè, Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Karyopharm, Novartis, Pfizer, Pharmamar, and Springworks; honoraria from Aadi, Glaxo, RainThera, and Pharmamar; support for attending meetings and travel from Pharmamar; participation on Data Safety Monitoring Board or Advisory Board for Bavarian Nordic, Pharmamar, Glaxo, Bayer, Daiichi, Epizyme, Maxivax, Novartis, Ikena; and unpaid leadership or fiduciary role in Italian Sarcoma Group, ESMO, Connective Tissue Oncology Society, EORTC, Chordoma Foundation, Desmoid Foundation, Epithelioid Hemagioendothelioma Foundation. F.L. reports employment with and stock and stock options in Daiichi Sankyo, Inc.

© 2022 Daiichi Sankyo Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Study design for the PL3397‐A‐U123 (Child–Pugh classification) and PL3397‐A‐U129 (NCI‐ODWG criteria) studies. D, day; HI, hepatic impairment; NCI‐ODWG, National Cancer Institute Organ Dysfunction Working Group; PK, pharmacokinetics.

Figure 2

Breakdown of severity of hepatic impairment based on Child–Pugh classification (blue) versus National Cancer Institute Organ Dysfunction Working Group criteria (orange). CP, Child–Pugh; NCI‐ODWG, National Cancer Institute Organ Dysfunction Working Group.

Figure 3

Mean (SD) plasma pexidartinib concentrations in subjects with (a) mild hepatic impairment (Child–Pugh A) and moderate hepatic impairment by (b) Child–Pugh B and (c) NCI‐ODWG, plotted in blue, versus subjects with normal hepatic function, plotted in orange, on a linear scale. h, hour; HI, hepatic impairment; NCI‐ODWG, National Cancer Institute Organ Dysfunction Working Group.

Figure 4

Mean (SD) plasma ZAAD‐1006a concentrations in subjects with (a) mild hepatic impairment (Child–Pugh A) and moderate hepatic impairment by (b) Child–Pugh B and (c) NCI‐ODWG, plotted in blue, versus subjects with normal hepatic function, plotted in orange, on a linear scale. h, hour; HI, hepatic impairment; NCI‐ODWG, National Cancer Institute Organ Dysfunction Working Group.