Evaluation of the pharmacokinetics of pemigatinib in patients with impaired hepatic or renal function.

AIMS: Pemigatinib, an inhibitor of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases, is approved for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma. Pemigatinib is predominantly metabolized by CYP3A4 with minimal renal elimination. METHODS: Separate hepatic and renal impairment studies were conducted to evaluate the effect of these impairments on pemigatinib pharmacokinetics (PK). Each study was of open-label, parallel-group design, conducted in participants with normal organ function and with hepatic or renal impairment. Plasma concentrations of pemigatinib were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS) and pemigatinib PK parameters were derived by noncompartmental analysis. Geometric mean ratios and two-sided 90% confidence intervals of Cmax , AUC0-t , and AUC0-∞ were compared by analysis of variance (ANOVA). RESULTS: Compared with healthy matched participants: Cmax and AUC0-∞ ratio (90% confidence interval) in participants with moderate hepatic impairment were 96.7% (59.4%, 157%) and 146% (100%, 212%), respectively; Cmax and AUC0-∞ ratio in participants with severe hepatic impairment were 94.2% (68.9%, 129%) and 174% (116%, 261%), respectively; Cmax and AUC0-∞ ratio in participants with severe renal impairment were 64.6% (44.1%, 94.4%) and 159% (95.4%, 264%), respectively; Cmax and AUC0-∞ ratio in participants with end-stage renal disease (ESRD) before haemodialysis (HD) were 77.5% (51.2%, 118%) and 76.8% (54.0%, 109%), respectively; Cmax and AUC0-∞ ratio in participants with ESRD after HD were 90.0% (59.3%, 137%) and 91.3% (64.1%, 130%), respectively. CONCLUSION: Pemigatinib dose should be reduced for patients with severe hepatic or renal impairment, and no dose adjustment is required for patients with moderate hepatic impairment or in ESRD patients undergoing HD.

Evaluation of drug-drug interactions of pemigatinib in healthy participants.

PURPOSE: Pemigatinib (INCB054828), a potent and selective oral fibroblast growth factor receptor 1-3 inhibitor, is a Biopharmaceutical Classification System class II compound with good permeability and pH-dependent solubility that is predominantly metabolized by cytochrome P450 (CYP) 3A. Two drug-drug interaction studies, one with acid-reducing agents, esomeprazole (proton pump inhibitor [PPI]) and ranitidine (histamine-2 [H2] antagonist), and the other with potent CYP3A-modulating agents, itraconazole (CYP3A inhibitor) and rifampin (CYP3A inducer), were performed. METHODS: Both were open-label, fixed-sequence studies conducted in up to 36 healthy participants each, enrolled into two cohorts (n = 18 each). Pemigatinib plasma concentration was measured, and pharmacokinetic parameters were derived by non-compartmental analysis. RESULTS: There was an 88% and 17% increase in pemigatinib area under the plasma drug concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), respectively, with itraconazole, and an 85% and 62% decrease in pemigatinib AUC and Cmax with rifampin coadministration. There was a 35% and 8% decrease in pemigatinib AUC and Cmax, respectively, with esomeprazole, and a 2% decrease in Cmax and 3% increase in AUC with ranitidine coadministration. In both studies, all adverse events reported were grade ≤ 2. CONCLUSION: Coadministration with itraconazole or rifampin resulted in a clinically significant change in pemigatinib exposure. Therefore, coadministration of strong CYP3A inducers with pemigatinib should be avoided, and the dose of pemigatinib should be reduced if coadministration with strong CYP3A inhibitors cannot be avoided. The effect of PPIs/H2 antagonists on pemigatinib exposure was modest, and pemigatinib can be administered without regard to coadministration of PPIs/H2 antagonists.