Chemical formula: C₂₅H₃₀N₆O₂ Molecular mass: 446.555 g/mol PubChem compound: 67462786
Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.
Erdafitinib increases serum phosphate concentration, a secondary effect of FGFR inhibition.
Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased in a dose-proportional manner across the dose range of 0.5 to 12 mg. Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold in patients with cancer. Following administration of 8 mg once daily, the proposed starting dose, mean (coefficient of variation [CV%]) erdafitinib steady-state Cmax, AUCτ, and minimum observed plasma concentration (Cmin) were 1399 ng/mL (50.8%), 29268 ng.h/mL (59.9%), and 936 ng/mL (64.9%) in patients with cancer. Daily fluctuations in erdafitinib plasma concentrations were low, with a mean (CV%) peak-to- trough ratio of 1.47 (23%) at steady state upon daily dosing.
After single dose oral administration, median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours) in healthy volunteers and oral absorption is near complete.
Administration of erdafitinib to healthy volunteers under fasting conditions and with a high-fat meal did not result in clinically relevant changes in Cmax and AUC. The mean AUC∞ and Cmax decreased by 6% and 14%, respectively, when erdafitinib is co-administered with a high-fat meal. Median time to reach tmax was delayed about 1.5 hours with food.
The mean apparent volume of distribution of erdafitinib in patients with cancer was 0.411 L/kg. Erdafitinib was 99.7% bound to human plasma proteins, preferentially to α1 acid glycoprotein.
Metabolism is the main route of elimination for erdafitinib. Erdafitinib is primarily metabolised in human by CYP2C9 and CYP3A4 to form the O demethylated major metabolite. 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.
Mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients with cancer. The mean effective half-life of erdafitinib in patients with cancer was 58.9 hours. Up to 16 days following a single oral administration of radiolabelled [14C]-erdafitinib, 69% of the dose was recovered in faeces (14-21% as unchanged erdafitinib) and 19% in urine (13% as unchanged erdafitinib) in healthy volunteers.
No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed based on age (21-92 years), sex, race (White, Hispanic or Asian), body weight (36-166 kg), mild or moderate renal impairment and mild or moderate hepatic impairment.
Pharmacokinetics of erdafitinib has not been studied in paediatric patients.
No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed between subjects with normal renal function (absolute GFR-MDRD [absolute glomerular filtration rate modification of diet in renal disease] ≥90 mL/min), and subjects with mild (absolute GFR‑MDRD 60 to 89 mL/min) and moderate renal impairment (absolute GFR‑MDRD 30 to 59 mL/min) based on population PK analysis. No information is available for subjects with severe renal impairment (absolute GFR‑MDRD less than 30 mL/min) or renal impairment requiring dialysis due to scarcity of PK data (n=7, 0.8%).
The pharmacokinetics of erdafitinib was examined in participants with preexisting mild n=8) or moderate n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control participants with normal hepatic function (n=8). The total AUC∞ were 82% and 61% in participants with mild and moderate hepatic impairment compared with participants with normal hepatic function, respectively. The total Cmax were 83% and 74% in participants with mild and moderate hepatic impairment compared with participants with normal hepatic function, respectively. The free AUC∞ were 95% and 88% in participants with mild and moderate hepatic impairment compared with participants with normal hepatic function, respectively. The free Cmax were 96% and 105% in participants with mild and moderate hepatic impairment compared with participants with normal hepatic function, respectively. No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function. The pharmacokinetics of erdafitinib in subjects with severe hepatic impairment is unknown due to limited data.
Erdafitinib is a substrate for P-gp. P-gp inhibitors are not expected to affect the PK of erdafitinib in a clinically relevant manner.
Erdafitinib has adequate solubility across the pH range of 1 to 7.4. Acid lowering agents (e.g., antacids, H2-antagonists, or proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.
No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed in patients taking sevelamer.
The main toxicological findings following repeat-dose administration of erdafitinib in both rats and dogs were related to the pharmacological activity of erdafitinib as an irreversible inhibitor of FGFR, including increased inorganic phosphorus and calcium in plasma, ectopic mineralisation in various organs and tissues, lesions in bone/cartilage at erdafitinib exposures lower than the human exposure at the recommended clinical dose. Corneal atrophy (thinning of the corneal epithelium) was seen in rats and lacrimal gland atrophy, changes to haircoat and nails as well as dental changes after 3 months of treatment was seen in rats and dogs. Disturbance of phosphate homeostasis was observed in rats and dogs at exposures less than the human exposures at all doses studied.
Soft tissue mineralisations (except for the aorta mineralisation in dogs) and chondroid dysplasia in rats and dogs and mammary gland atrophy in rats were partially to fully recovered at the end of a 4-week drug-free recovery period.
Erdafitinib is an intrinsic human ether-à-go-go-related gene (hERG) blocker with a proarrhythmic liability which translated into a prolonged repolarisation (corrected QT interval) after intravenous dosing in the anaesthetised dog and guinea pig, and after oral dosing in the conscious dog. The no effect level represents a safety margin of 2.4 relative to the clinical steady-state free maximum plasma concentration (Cmax,u) for a 9 mg once daily dose.
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of erdafitinib. Erdafitinib was considered not genotoxic in the standard panel of good laboratory practice (GLP) genotoxicity assays.
Erdafitinib was teratogenic and embryotoxic in rats at exposures less than the human exposures. Foetal toxicity was characterised by hand/foot defects and malformations of some major blood vessels, such as the aorta.
Dedicated animal fertility studies have not been conducted with erdafitinib. However, in the 3-month general toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the corpora lutea) in rats at an exposure approximating the AUC in patients at maximum recommended dose of 9 mg, QD.
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