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

Abstract

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 (AUC 0-24,ss). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC 0-24,ss were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC 0-24,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.

Exposure–response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor

“…PK data were analyzed using population PK (PopPK) modeling previously described to obtain exposure metrics in individual patients 5 …”

“…PK data were analyzed using population PK (PopPK) modeling previously described to obtain exposure metrics in individual patients. 5 The primary exposure metric in the exposure–response analysis was the PopPK model, which predicted the average drug concentration (C avg ) during 25 weeks of dosing. Efficacy end points were longitudinal tumor size and tumor response assessed using RECIST (version 1.1) and TVS by blinded independent central review.…”

Pexidartinib: first approved systemic therapy for patients with tenosynovial giant cell tumor

“…Following oral administration, pexidartinib is rapidly absorbed, with a median time to maximum plasma concentration (T max ) of approximately 2.5 h and a mean half-life of approximately 27 h [19]. When pexidartinib is administered as a single oral dose, the exposure increased linearly over a dose range of 200-2400 mg. At steady state, at a dosage of 400 mg twice daily, the mean (standard deviation [SD]) maximum serum concentration (C max ) was 8625 (2746) ng/ml; the mean (SD) area under the concentration-time curve from 0-12 h (AUC 0-12 h ) was 77,465 (24,975) ng/h/ml [19]. Although the clinical studies had a 2-week loading dose of 1000 mg per day, an exposure-response analysis supported the administration of 800 mg/day without a loading dose for patients with TGCT [23].…”

“…When pexidartinib was administered with a high-fat meal, median time to T max was delayed by approximately 2.5 h, while administering pexidartinib with a low-fat meal delayed T max by 1.5 h. These findings highlight the importance of taking pexidartinib on an empty stomach at least 1 h before or 2 h after a meal or snack [19]. A pharmacokinetic model that included healthy volunteers and patients from a Phase I study and the Phase III ENLIVEN study in patients with TGCT identified no clinically meaningful effects of pexidartinib exposure for demographic characteristics (such as race, healthy volunteers vs patients) or renal and hepatic functional parameters [24]. Similarly, a population pharmacokinetics analysis showed similar exposures between Asian and non-Asian patients [25].…”

Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability

“…Few studies have been recently published for the quantitative determination of PX in pharmaceutical products using HPLC [ 16 ], in plasma to study PX population pharmacokinetics [ 17 ] and pediatric pharmacokinetics/ pharmacodynamics [ 15 ], in cerebrospinal fluids to measure its brain uptake [ 18 ] and in drug-drug interaction, studies using LC-MS/MS [ 11 ]. However, these studies lack the details of the methods chromatographic parameters and extraction techniques.…”