PEMAZYRE Tablet Ref.[10156] Active ingredients: Pemigatinib

Cardiac Electrophysiology

At a dose 1.5 times the maximum recommended dose, PEMAZYRE does not result in a large mean increase (i.e. >20 ms) of the QTc interval.

Serum Phosphate

Pemigatinib increased serum phosphate levels as a consequence of FGFR inhibition. In patients, the increase in serum phosphate observed after treatment with pemigatinib was exposure-dependent across the dose range of 1 to 20 mg once daily (0.07 to 1.5 times the recommended dose), with increased risk of hyperphosphatemia with higher pemigatinib exposure.

The geometric mean steady-state pemigatinib AUC_0-24h was 2620 nM·h (54% CV) and C_max was 236 nM (56% CV) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of 1 to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within 4 days following repeated once daily dosing. With repeated once daily dosing, pemigatinib accumulated with a median accumulation ratio of 1.63 (range 0.63 to 3.28).

Absorption

The median time to achieve peak pemigatinib plasma concentration (T_max) was 1.13 (0.50‑6.00) hours.

Effect of Food

Administration of PEMAZYRE with a high-fat and high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500‑600 calories from fat) had no clinically meaningful effect on pemigatinib pharmacokinetics.

Distribution

The estimated apparent volume of distribution was 235 L (60.8%) following a 13.5 mg oral dose. In vitro, pemigatinib was 90.6% bound to human plasma proteins at concentrations ranging from 1 to 10 µM.

Elimination

The geometric mean elimination half-life (t_½) of pemigatinib was 15.4 (51.6% CV) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV).

Metabolism

Pemigatinib is predominantly metabolized by CYP3A4 in vitro. The major drug-related moiety in plasma was unchanged pemigatinib in a human [¹⁴C] mass balance study.

Excretion

Following a single oral 11 mg dose of radiolabeled pemigatinib, 82.4% of the dose was recovered in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).

Specific Populations

No clinically meaningful differences in the systemic exposure of pemigatinib were observed based on age (21‑79 years), sex, race/ethnicity, body weight (39.8‑156 kg), mild to moderate renal impairment, or mild to moderate hepatic impairment. The effect of severe renal impairment, renal dialysis in end-stage renal disease, or severe hepatic impairment on pemigatinib exposure is unknown.

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Effect of CYP3A Inhibitors on Pemigatinib: Itraconazole, a strong CYP3A inhibitor, increased C_max by 17% and increased AUC by 88% following a single oral PEMAZYRE dose of 4.5 mg [see Drug Interactions (7.1)].

Concomitant use of moderate CYP3A inhibitors is predicted to increase pemigatinib exposure by approximately 50-80% [see Drug Interactions (7.1)].

Effect of CYP3A Inducers on Pemigatinib: Rifampin, a strong CYP3A inducer, decreased pemigatinib C_max by 62% and AUC by 85% following a single oral PEMAZYRE dose of 13.5 mg [see Drug Interactions (7.1)]. Concomitant use of a moderate CYP3A inducer is predicted to decrease pemigatinib exposure by more than 50% [see Drug Interactions (7.1)].

Effect of Acid-Lowering Agents on Pemigatinib: Esomeprazole, a proton pump inhibitor, decreased pemigatinib C_max by 35% and AUC by 8% following a single oral PEMAZYRE dose of 13.5 mg; these differences are not expected to be clinically meaningful. Ranitidine, a histamine-2 antagonist, did not affect pemigatinib exposure.

Other Drugs: No clinically significant differences in glucose levels were observed when metformin (OCT2/MATE1 substrate) was co-administered with pemigatinib.

In Vitro Studies

Effect of Pemigatinib on CYP Enzymes: Pemigatinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or an inducer of CYP1A2, CYP2B6, or CYP3A4.

Pemigatinib as a Substrate for Transporters: 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.

Effect of Pemigatinib on Transporters: Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. Pemigatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function [see Adverse Reactions (6.1)].

Carcinogenicity studies have not been conducted with pemigatinib.

Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rats.

Dedicated fertility studies with pemigatinib have not been conducted. Oral administration of pemigatinib did not result in any dose-related findings likely to result in impaired fertility in male and female reproductive organs.

14.1 Cholangiocarcinoma

FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial, evaluated the efficacy of PEMAZYRE in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least 1 prior therapy and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by a clinical trial assay performed at a central laboratory. Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact.

Patients received PEMAZYRE in 21-day cycles at a dosage of 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy. PEMAZYRE was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1.

The median age was 56 years (range: 26 to 77 years), 61% were female, 74% were White, and 95% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (42%) or 1 (53%). Ninety-eight percent of patients had intrahepatic cholangiocarcinoma. Eighty-six percent of patients had in-frame FGFR2 gene fusions and the most commonly identified FGFR2 fusion was FGFR2-BICC1 (34%). Fourteen percent of patients had other FGFR2 rearrangements that could not be confidently predicted to be in-frame fusions, including rearrangements without an identifiable partner gene. All patients had received at least 1 prior line of systemic therapy, 27% had 2 prior lines of therapy, and 12% had 3 or more prior lines of therapy. Ninety-six percent of patients had received prior platinum-based therapy including 76% with prior gemcitabine/cisplatin.

Efficacy results are summarized in Table 5.

The median time to response was 2.7 months (range 0.7–6.9 months).

Table 5. Efficacy Results in FIGHT-202:

* The 95% confidence interval (CI) was calculated using the Brookmeyer and Crowley’s method.
Note: Data are from IRC per RECIST v1.1, and complete and partial responses are confirm