Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EN02 
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).

Pharmacodynamic effects

Serum phosphate
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 (see sections 4.2, 4.4 and 4.8).

Clinical studies
FIGHT-202 was a multicentre, open-label, single-arm study to evaluate the efficacy and safety of Pemazyre in previously treated patients with locally advanced/metastatic or surgically unresectable cholangiocarcinoma. The efficacy population consists of 108 patients (107 patients with intrahepatic disease) that had progressed after at least 1 prior therapy and who had FGFR2 fusion or rearrangement, as determined by the test performed at a central laboratory.

Patients received Pemazyre in 21-days cycles consisting of 13.5 mg once daily oral dosing for 14 days, followed by 7 days off therapy. Pemazyre was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), as determined by independent review committee (IRC) according to RECIST v1.1.

The median age was 55.5 years (range: 26 to 77 years), 23.1 % were ≥65 years, 61.1 % were female, and 73.1 % were Caucasian. Most (95.4 %) patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (42.6 %) or 1 (52.8 %). All patients had at least 1 prior line of systemic therapy, 27.8 % had 2 prior lines of therapy, and 12.0 % had 3 or more prior lines of therapy.
Ninety-six percent of patients had received prior platinum-based therapy including 78 % with prior gemcitabine/cisplatin.

Efficacy results are summarised in table 5.

The median time to response was 2.69 months (range 0.7 – 16.6 months).


Table 5:           Efficacy results
Cohort A (FGFR2 fusion or rearrangement)
Efficacy Evaluable Population
(N = 108)
ORR (95 % CI)                                                             37.0 % (27.94, 46.86) Complete response (N)                                                       2.8 % (3) Partial response (N)                                                       34.3 % (37) Median duration of response (months) (95 %                                 9.13 (6.01, 14.49) CI)a
Kaplan-Meier estimates of duration of response (95 % CI)
3 months                                                                100.0 (100.0, 100.0) 6 months                                                                  67.8 (50.4, 80.3) 9 months                                                                  50.5 (33.3, 65.4) 12 months                                                                 41.2 (24.8, 56.8) ORR- CR+PR
CI= Confidence Interval
Note: Data are from IRC per RECIST v1.1, and complete and partial responses are confirmed.
a The 95 % CI was calculated using the Brookmeyer and Crowley's method 

Elderly patients
In the clinical study of pemigatinib, 23.1 % of patients were 65 years and older, and 4.6 % of patients were 75 years and older. No difference in efficacy response was detected between these patients and in patients < 65 years of age.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Pemazyre in all subsets of the paediatric population in the treatment of cholangiocarcinoma. See section 4.2 for information in pediatric use.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Pemigatinib exhibits linear pharmacokinetics in the dose range of 1 to 20 mg. Following oral administration of Pemazyre 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.

Absorption
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.

Distribution
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.

Biotransformation
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.


Elimination
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).

Excretion
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).

Renal impairment
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 (see section 4.2).
Hepatic 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 (see section 4.2).
Interactions

CYP substrates
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.

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.

In vitro, pemigatinib is an inhibitor of OATP1B3, OCT2, and MATE1. Inhibition of OCT2 may increase serum creatinine.