Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug–Drug Interaction Study
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Background and Objectives
Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated.
In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1–11, or Treatment C (itraconazole 200 mg/day orally) on days 1–11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration–time data using standard non-compartmental methods.
Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults.
Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential.
ClinicalTrials.gov identifier number: NCT03135106.
Investigational compound erdafitinib (JNJ-42756493) was discovered in collaboration with Astex Pharmaceuticals. This study was supported by Janssen Research & Development, LLC. The authors thank all the volunteers for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff. The authors also thank Jan de Jong (Janssen Research & Development, LLC) for his contribution in the study design, data analysis and interpretation, and Yvonne Lau for review of the manuscript. Writing assistance was provided by Ramji Narayanan, M Pharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd.) funded by Janssen Global Services and additional editorial support for this manuscript was provided by Harry Ma, PhD (Janssen Global Services, LLC).
First and second authors have equally contributed to this manuscript. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to this journal.
Compliance with Ethical Standards
Janssen Research & Development LLC.
Conflict of interest
All authors were employees of Janssen Research & Development, LLC.
The study protocol and amendments were approved by an Independent Ethics Committee. The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and consistent with the International Conference on Harmonization, Good Clinical Practice guidelines, and applicable regulatory requirements.
Written informed consent was obtained from all individuals to participate in the study.
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