Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors

• Published in: Journal of clinical pharmacology Vol. 61; no. 4; pp. 480 - 492
• Main Authors: Yin, Ophelia, Wagner, Andrew J., Kang, Jia, Knebel, William, Zahir, Hamim, Sande, Michiel, Tap, William D., Gelderblom, Hans, Healey, John H., Shuster, Dale, Stacchiotti, Silvia
• Format: Journal Article
• Language: English
• Published: England 01.04.2021
• Subjects: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aminopyridines - pharmacokinetics; Aminopyridines - therapeutic use; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Asians; Bacterial Proteins; Body Weight; Creatinine - blood; Female; Giant Cell Tumor of Tendon Sheath - drug therapy; Giant Cell Tumor of Tendon Sheath - pathology; Humans; Kidney Function Tests; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; pexidartinib; pharmacokinetics; population pharmacokinetics; Pyrroles - pharmacokinetics; Pyrroles - therapeutic use; Racial Groups; Sex Factors; Sociodemographic Factors; TGCT; Tumor Burden; Young Adult; ZAAD; pharmacokinetics; TGCT; ZAAD; PK; pexidartinib; population pharmacokinetics
• DOI: 10.1002/jcph.1753
• ISSN: 0091-2700

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2‐compartment model with sequential zero‐ and first‐order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non‐Asian, weight = 80 kg, creatinine clearance ≥90 mL/min, aspartate aminotransferase ≤80 U/L, and total bilirubin ≤20.5 μmol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady‐state area under the curve values from 0 to 24 hours (AUC0‐24,ss). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC0‐24,ss were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC0‐24,ss than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles.