ferences with erdafitinib pharmacokinetics were observed followingadministration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately50% 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 andCYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively.
Unchangederdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.
ExcretionFollowing a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recoveredin 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 (2188 years), sex, race, body weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, usingmodification of diet in renal disease equation] 60 to 89 mL/min/1.73 m²) or moderate (eGFR 30-59mL/min/1.73 m²) renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN,or total bilirubin > 1.0–1.5 x ULN and any AST).
The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring
dialysis, moderate or severe hepatic impairment is unknown.
Drug Interaction Studies
Clinical Studies and Model-Based Approaches
Strong 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 strong CYP2C9 inhibitor and moderate CYP3A4inhibitor, 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.
Strong CYP3A4/2C9 Inducers:
Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decreaseerdafitinib Cmax and AUC.
In Vitro Studies
CYP Substrates:
Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitiveCYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinicallyrelevant concentrations.
Transporters:
Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinibexposure 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-2Kat 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 th |
