032: Effect of Carbamazepine, a CYP29C & 3A4 Inducer, on the Pharmacokinetics of Erdafitinib (Balversa®): A Phase I Drug-Drug Interaction Study in Healthy Adult Participants

Statement of Purpose: Erdafitinib (Balversa®) is a selective and potent oral pan-FGFR inhibitor approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum based chemotherapy. Erdafitinib elimination occurs mainly through CYP2C9 and CYP3A4 metabolism. The study investigated the drug-drug interaction (DDI) potential of erdafitinib when coadministered with multiple doses of carbamazepine, a strong inducer of CYP3A and a weak inducer of CYP2C9.

Description of Methods & Materials: This was a Phase I, open-label, single sequence, DDI study conducted to investigate the effect of multiple doses of carbamazepine on the single 12 mg dose pharmacokinetics (PK) of erdafitinib in healthy adult participants. The study consisted of 2 study periods. In Period 1, participants received a single-dose intake of erdafitinib (12 mg). In Period 2, participants received another 12 mg single dose of erdafitinib while taking repeated doses of carbamazepine (titrated up from 100 mg every 12 h to 300 mg every 12 h) for 21 consecutive days (co-administration after 14 days). The safety of a single 12 mg oral dose of erdafitinib administered with or without carbamazepine was evaluated as a secondary objective.

Data & Results: Statistical analysis of PK data included data from 13 participants. Multiple doses of carbamazepine induced CYP2C9 and CYP3A4-mediated metabolism of erdafitinib, resulting in significantly reduced plasma exposures of both total and free erdafitinib. Compared with when erdafitinib was administered alone, carbamazepine administration decreased total and free maximum plasma concentrations of erdafitinib (C_max) by 35% (CI 30%-39%) and 22% (CI 17%-27%), respectively. For areas under the concentration–time curve over the time interval from 0 to 168 h, to the last quantifiable data point, and to time infinity (AUC168h, AUC_last, AUC_∞), this decrease ranged from 56% to 62% for total erdafitinib and from 48% to 55% for free erdafitinib. The administration of a single 12 mg oral dose of erdafitinib was safe and acceptably well tolerated, both when administered with or without carbamazepine.

Interpretation, Conclusion or Significance: Induction of liver CYPs enzymes typically accelerates metabolism of drugs that are eliminated via CYP metabolism, thus decreasing the substrate drug’s systemic exposure and consequently may influence the overall clinical effectiveness of a drug. Coadministration of erdafitinib with a strong inducer of CYP3A4 and weak inducer of CYP2C9 such as carbamazepine led to markedly reduced plasma exposure of erdafitinib. Therefore, coadministration of CYP2C9 inducers or strong CYP3A4 inducers with erdafitinib should be avoided.

Disclosures: Pharavee Jaiprasart, Juhui James Jiao, Anne-Gaëlle Dosne, Lien Vandenberk, Wei Zhu, Peter Hellemans own stock in Johnson & Johnson. Erdafitinib was developed in collaboration with Astex.