Population Pharmacokinetics Analysis of Pemigatinib in Patients With Advanced Malignancies

Abstract

Pemigatinib is a fibroblast growth factor receptor 1–3 inhibitor used to treat cholangiocarcinoma. A compartmental population pharmacokinetics model was developed using data from 318 patients with cancer enrolled in a phase 1 dose-escalation/dose-expansion study, a phase 1 Japanese PK bridging study, and a phase 2 cholangiocarcinoma study. The final model for pemigatinib was a 2-compartment disposition model with first-order absorption and linear elimination. All fixed- and random-effect parameters were estimated with good precision, and no apparent biases in the overall model fit were observed. For females, the estimated typical pemigatinib absorption rate constant (ka) and oral clearance (CL/F) were estimated (1.49 L/h and 10.3 L/h, respectively). For males, the typical apparent clearance and ka are 19.0% higher and 56.5% lower, respectively, compared with females. Typical apparent volume of distribution of the central compartment (Vc/F) and peripheral compartment for a 73.3-kg patient was estimated to be 122.0 L and 80.1 L, respectively; both increased with body weight. Phosphate binder coadministration decreases typical pemigatinib CL/F by 14.1%. Proton pump inhibitor coadministration increases typical pemigatinib apparent Vc/F by 24.4%. Phosphate binders and sex contribute a <20% change to CL/F. The impact of the investigated covariates on pemigatinib pharmacokinetics are not clinically significant.