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

Abstract

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 C max , AUC 0-t , and AUC 0-∞ were compared by analysis of variance (ANOVA).Results: Compared with healthy matched participants: C max and AUC 0-∞ ratio (90% confidence interval) in participants with moderate hepatic impairment were 96.7% (59.4%, 157%) and 146% (100%, 212%), respectively; C max and AUC 0-∞ ratio in participants with severe hepatic impairment were 94.2% (68.9%, 129%) and 174% (116%, 261%), respectively; C max and AUC 0-∞ ratio in participants with severe renal impairment were 64.6% (44.1%, 94.4%) and 159% (95.4%, 264%), respectively;C max and AUC 0-∞ 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; C max and AUC 0-∞ 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.

Population Pharmacokinetics Analysis of Pemigatinib in Patients With Advanced Malignancies

“…The geometric mean CL/F of 10.9 L/h in this analysis is comparable to those calculated by the noncompartmental analysis approach (geometric mean CL/F ranged from 9.88 to 11.7 L/h) in the phase 1 dose-escalation and dose-expansion study. 16 As the renal clearance of pemigatinib is low (1% of total clearance), 18 a clinically significant effect of mild and moderate renal impairment on the pemigatinib PK was not expected. In the current study, mild and moderate renal impairment were not found to be statistically significant predictors for CL/F.…”

“…Analysis of plasma samples was performed using a validated, liquid chromatography-tandem mass spectrometry method previously described in Ji T, et al 18 The assay had a linear range of 1 nM (0.488 ng/mL) to 1000 S1). To overcome the limitations of a small sample size, a specific drug interaction analysis was performed only if ≥5% of the patient population were on the concomitant medication involved.…”

“…18 The exposure difference between patients with end-stage renal disease before or after hemodialysis and patients with normal renal function (geometric mean ratio of 76.8% and 91.3%, respectively) was not clinically meaningful. 18 The effect of food on pemigatinib was modest; in a fed state, the median time to C max was delayed by 4.02 hours postdose, which was statistically significant compared with the fed state (P = 0.0013). However, this observed effect of high-fat and high-calorie diet on pemigatinib steady state was not clinically significant (data on file).…”

“…A hepatic impairment study showed that there was evidence of a clinically significant pemigatinib AUC increase (74%) for patients with severe hepatic impairment, and pemigatinib AUC increase (46%) for patients with moderate hepatic impairment is covered by safety margin (therapeutic dose of 13.5 mg once daily and highest safe dose of 20 mg once daily) 18 . A renal impairment study showed that there was evidence of a clinically significant pemigatinib AUC increase (59%) for patients with severe renal impairment 18 . The exposure difference between patients with end‐stage renal disease before or after hemodialysis and patients with normal renal function (geometric mean ratio of 76.8% and 91.3%, respectively) was not clinically meaningful 18 …”

“…18 A renal impairment study showed that there was evidence of a clinically significant pemigatinib AUC increase (59%) for patients with severe renal impairment. 18 The exposure difference between patients with end-stage renal disease before or after hemodialysis and patients with normal renal function (geometric mean ratio of 76.8% and 91.3%, respectively) was not clinically meaningful. 18 The effect of food on pemigatinib was modest; in a fed state, the median time to C max was delayed by 4.02 hours postdose, which was statistically significant compared with the fed state (P = 0.0013).…”