Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics
Cardiac Electrophysiology
Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval.
Serum Phosphate
Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition.
BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5-7.0 mg/dL in early cycles with continuous daily dosing [see Dosage and Administration (5.3)].
In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate- containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels [see Drug Interactions (9.1)].

Pharmacokinetic Properties

12.3   Pharmacokinetics
Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively.


Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold.
Absorption
Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours).
Effect of Food
No clinically meaningful differences with erdafitinib 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 healthy subjects.

Distribution
The mean apparent volume of distribution of erdafitinib was 29 L in patients.
Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein.

Elimination
The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients.
The mean effective half-life of erdafitinib was 59 hours in patients.
Metabolism
Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20%, respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.
Excretion
Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).
Specific Populations
No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21-88 years), sex, race, body weight (36-132 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²). Limited data are available in patients with severe (Child-Pugh C) hepatic impairment. The pharmacokinetics of erdafitinib in patients with severe renal impairment and renal impairment requiring dialysis is unknown.


Drug Interaction Studies
Clinical Studies
Effect of Other Drugs on erdafitinib
Moderate CYP2C9 Inhibitors:
Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, relative to erdafitinib alone.
Strong CYP3A4 Inhibitors:
Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone.
CYP3A4/2C9 Inducers:
Mean ratios (90% CI) of Cmax and AUCinf for free erdafitinib were 78% (72.76, 83.12) and 45% (39.74, 51.59), respectively, when co-administered with carbamazepine (a strong
CYP3A4 and weak CYP2C9 inducer) relative to erdafitinib alone [see Interactions (7.1)].
Effect of Erdafitinib on Other Drugs
CYP3A4 Substrates:
Mean ratios (90% CI) of Cmax and AUCinf for midazolam (a sensitive CYP3A4 substrate) were 86.29% (73.52, 101.28) and 82.11% (70.83, 95.18), respectively, when co- administered with erdafitinib relative to midazolam alone. Erdafitinib does not have a clinically meaningful effect on midazolam PK.
OCT2 Substrates:

Mean ratios (90% CI) of Cmax and AUCinf for metformin (a sensitive OCT2 substrate) were 108.66% (90.31, 130.75) and 113.92% (93.22, 139.23), respectively, when co- administered with erdafitinib relative to metformin alone. Erdafitinib does not have a clinically meaningful effect on metformin PK.
In Vitro Studies
CYP Substrates:
Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.
Transporters:
Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent. Erdafitinib is an inhibitor of OCT2.

Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations.
Acid-Lowering Agents:
Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid-lowering agents (e.g., antacids, H2-antagonists, proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.
12.5   Pharmacogenomics
CYP2C9 activity is reduced in individuals with genetic variants, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Erdafitinib exposure was similar in subjects with CYP2C9*1/*2 and *1/*3 genotypes relative to subjects with CYP2C9*1/*1 genotype (wild type). No data are available in subjects characterized by other genotypes (e.g., *2/*2, *2/*3, *3/*3). Simulation suggested no clinically meaningful differences in erdafitinib exposure in subjects with CYP2C9*2/*2 and *2/*3 genotypes. The exposure of erdafitinib is predicted to be 50% higher in subjects with the CYP2C9*3/*3 genotype, estimated to be present in 0.4% to 3% of the population among various ethnic groups.