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Effect of Erdafitinib on the Pharmacokinetics of Midazolam and Metformin in Patients With Advanced Solid Tumors Harboring FGFR Gene Alterations.
- Source :
-
Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2024 Oct; Vol. 13 (10), pp. 1164-1176. Date of Electronic Publication: 2024 Jul 24. - Publication Year :
- 2024
-
Abstract
- Erdafitinib, an oral pan-FGFR inhibitor, is used in locally advanced or metastatic urothelial carcinoma for adults with FGFR3 genetic alterations and whose disease progressed following prior systemic therapy. This drug-drug interaction substudy evaluated the effect of erdafitinib on the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate), and metformin (organic cation transporter 2 substrate). Twenty-five patients with advanced solid tumors harboring FGFR gene alterations received pretreatment with single doses of midazolam and metformin, followed by a daily dose of erdafitinib. Drug-drug interaction assessments were performed at erdafitinib steady state following coadministration of single doses of midazolam and metformin, respectively. Geometric mean ratios for maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were estimated using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). The 90% confidence intervals of geometric mean ratios for maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity of midazolam (86.3%, 88.5%, and 82.1%), 1-OH midazolam (99.8%, 97.4%, and 101.5%), and metformin (108.7%, 119.0%, and 113.9%) were either contained or slightly outside the 80%-125% interval and not considered clinically meaningful. Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin.<br /> (© 2024 Janssen Research & Development, LLC. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Subjects :
- Humans
Male
Female
Middle Aged
Aged
Adult
Pyrazoles pharmacokinetics
Pyrazoles adverse effects
Pyrazoles administration & dosage
Quinoxalines pharmacokinetics
Quinoxalines administration & dosage
Quinoxalines adverse effects
Receptor, Fibroblast Growth Factor, Type 3 genetics
Receptor, Fibroblast Growth Factor, Type 3 antagonists & inhibitors
Cytochrome P-450 CYP3A genetics
Cytochrome P-450 CYP3A metabolism
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Midazolam pharmacokinetics
Midazolam administration & dosage
Metformin pharmacokinetics
Metformin administration & dosage
Metformin adverse effects
Metformin pharmacology
Drug Interactions
Neoplasms drug therapy
Neoplasms genetics
Area Under Curve
Subjects
Details
- Language :
- English
- ISSN :
- 2160-7648
- Volume :
- 13
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology in drug development
- Publication Type :
- Academic Journal
- Accession number :
- 39044705
- Full Text :
- https://doi.org/10.1002/cpdd.1445