Effect of Carbamazepine on the Pharmacokinetics of Erdafitinib in Healthy Participants.

Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided.

Jaiprasart P ，Hellemans P ，Jiao JJ ，Dosne AG ，De Meulder M ，De Zwart L ，Brees L ，Zhu W ... -  《Clinical Pharmacology in Drug Development》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Phase 1 drug-drug interaction study to assess the effect of CYP3A4 inhibition and pan-CYP induction on the pharmacokinetics and safety of fosmanogepix in healthy participants.

Hodges MR ，van Marle S ，Kramer WG ，Ople E ，Tawadrous M ，Jakate A ... -  《-》

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

Poggesi I ，Li LY ，Jiao J ，Hellemans P ，Rasschaert F ，de Zwart L ，Snoeys J ，De Meulder M ，Mamidi RNVS ，Ouellet D ... -  《-》

The effect of carbamazepine, a strong CYP3A inducer, on the pharmacokinetics of zongertinib in healthy male volunteers.

Zongertinib (BI 1810631) is a potent, selective, and epidermal growth factor receptor (EGFR) wild-type sparing human epidermal growth factor receptor 2 (HER2) inhibitor. Based on in vitro data, the oxidative hepatic metabolism of zongertinib is principally driven by cytochrome P450 (CYP) 3A4/5. Therefore, zongertinib may be affected by strong CYP3A inducers, like carbamazepine. This study aimed to investigate the effect of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zongertinib in healthy male subjects. This open-label, two-period, fixed-sequence clinical drug-drug interaction study examined the pharmacokinetics of a single 60-mg oral dose of zongertinib in the absence or presence of multiple oral doses of carbamazepine. The extent of drug-drug interaction was estimated using the adjusted geometric mean ratios (and 90% confidence intervals [CIs]) for the test treatment (zongertinib in the presence of carbamazepine) versus the reference treatment (zongertinib alone) for areas under the plasma concentration-time curve from time 0 to infinity and to the last quantifiable time point (AUC0-∞, AUC0-tz) and maximum measured plasma concentration (Cmax). Sixteen subjects (all Caucasian males) received zongertinib alone in Study Period 1, and 15 of them received both zongertinib and carbamazepine in Study Period 2. Upon co-administration with carbamazepine in Study Period 2, AUC0-∞ and AUC0-tz of zongertinib were both reduced to 36.5% (90% CI: 32.0%-41.6% for AUC0-∞ and 31.9%-41.7% for AUC0-tz). The Cmax of zongertinib was reduced to 56.4% (90% CI: 45.1%-70.6%). Zongertinib exposure was reduced by 63.5% when coadministered with the strong CYP3A inducer, carbamazepine.

Tian X ，Esmaeili H ，Minich D ，Seitz F ，Roessner PM ，Wind S ，Grempler R ，Gan G ，Chan TS ，Mahmoudi M ，Sadrolhefazi B ，Müller F ... -  《-》