Molecular mass: 487.508 g/mol
Pemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation and signalling and decreases cell viability in cells expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements. FGFR2 fusions/rearrangements are strong oncogenic drivers and are the most common FGFR alteration occurring, almost exclusively, in 10-16% of intrahepatic cholangiocarcinoma (CCA).
Pemigatinib increased serum phosphate level as a consequence of FGFR inhibition. In pemigatinib clinical studies, phosphate-lowering therapy and dose modifications were permitted to manage hyperphosphataemia.
Pemigatinib exhibits linear pharmacokinetics in the dose range of 1 to 20 mg. Following oral administration of pemigatinib 13.5 mg once daily, steady-state was reached by 4 days with a geometric mean accumulation ratio of 1.6. The geometric mean steady-state AUC0-24h was 2620 nM·h (54% CV) and Cmax was 236 nM (56% CV) for 13.5 mg once daily.
Median time to achieve peak plasma concentration (tmax) was 1 to 2 hours. No clinically meaningful differences with pemigatinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in patients with cancer.
Pemigatinib is 90.6% bound to human plasma proteins, predominantly to albumin. The estimated apparent volume of distribution was 235 L (60.8%) in patients with cancer.
Pemigatinib is predominantly metabolised by CYP3A4 in vitro. Following oral administration of a single 13.5 mg radiolabeled pemigatinib dose, unchanged pemigatinib was the major drug-related moiety in plasma, and no metabolites >10% of total circulating radioactivity were observed.
Following oral administration of pemigatinib 13.5 mg once daily in patients with cancer, the geometric mean elimination half-life (t½) was 15.4 (51.6% CV) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV).
Following a single oral dose of radiolabeled pemigatinib, 82.4% of the dose was recovered in faeces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).
The effect of renal impairment on the pharmacokinetics of pemigatinib was evaluated in a renal impairment study in subjects with normal renal function (GFR ≥90 mL/min), severe renal function (GFR <30 mL/min and not on hemodialysis) and End Stage Renal Disease (ESRD) (GFR <30 mL/min and on hemodialysis). In subjects with the severe renal impairment, the geometric mean ratios (90% CI) compared to normal controls were 64.6% (44.1%, 94.4%) for Cmax and 159% (95.4%, 264%) for AUC0-∞. In the subjects with ESRD before hemodialysis, the geometric mean ratios (90% CI) was 77.5% (51.2%, 118%) for Cmax and 76.8% (54.0%, 109%) for AUC0-∞. Besides, in participants with ESRD after hemodialysis, the geometric mean ratios (90% CI) were 90.0% (59.3%, 137%) for Cmax and 91.3% (64.1%, 130%) for AUC0-∞. Based on these results, pemigatinib dose should be reduced for patients with severe renal impairment.
The effect of hepatic impairment on the pharmacokinetics of pemigatinib was evaluated in a hepatic impairment study in subjects with normal hepatic function, moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. In subjects with moderate hepatic impairment, the geometric mean ratios (90% CI) compared to normal controls, were 96.7% (59.4%, 157%) for Cmax and 146% (100%, 212%) for AUC0-∞.In subjects with severe hepatic impairment, the GMR (90% CI) was 94.2% (68.9%, 129%) for Cmax and 174% (116%, 261%) for AUC0-∞. Based on these results, no dose adjustment is recommended for patients with mild and moderate hepatic impairment. However, pemigatinib dose should be reduced for patients with severe hepatic impairment.
Pemigatinib at clinically relevant concentrations is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 or an inducer of CYP1A2 and CYP3A4.
Pemigatinib is a substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affect pemigatinib exposure at clinically relevant concentrations.
In vitro, pemigatinib is an inhibitor of OATP1B3, OCT2, and MATE1. Inhibition of OCT2 may increase serum creatinine.
The most prominent findings following repeat-dose administration of pemigatinib in both rats and monkeys were attributed to the intended pharmacology of pemigatinib (FGFR1, FGFR2, and FGFR3 inhibition), including hyperphosphataemia, physeal dysplasia, and soft tissue mineralization; some of these findings were observed at exposures (AUC) lower than therapeutic. Mineralization was observed in numerous tissues including kidneys, stomach, arteries, ovaries (monkey only), and eyes (cornea, rat only). Soft tissue mineralization was not reversible, while physeal and cartilage findings were reversible. In addition, changes of the bone marrow (rats) and kidney lesions were observed.
Pemigatinib was not mutagenic in a bacterial mutagenicity assay, nor clastogenic in an in vitro chromosome aberration assay, and did not result in induction of bone marrow micronuclei in an in vivo micronucleus assay in rats.
Carcinogenicity studies with pemigatinib have not been conducted. Impairment of fertility No specific animal studies with pemigatinib have been conducted to evaluate the effects of pemigatinib on fertility. In repeated dose toxicity studies, oral administration of pemigatinib did not result in any dose-related adverse effects on male and female reproductive organs.
In rats, administration of pemigatinib at ≥0.3 mg/kg/day during the period of organogenesis resulted in 100% postimplantation loss. At 0.1 mg/kg/day, an increase in foetal skeletal malformations and major blood vessels variations, reduced ossification, and decrease foetal body weight were observed. Exposure at that dose is approximately 20% of the clinical exposure at the maximum recommended human dose of 13.5 mg based on AUC.
In vitro, pemigatinib showed an IC50 for hERG inhibition >8 μM (the highest feasible concentration based on solubility), that is >360-fold higher than the clinical steady-state unbound Cmax at the dose of 13.5 mg. In vivo, there were no adverse findings in safety pharmacology assessments of pemigatinib, including in vivo respiratory and central nervous system function studies in rats and cardiovascular study in monkeys.
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