Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors

Abstract

Background: A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032.

Methods: This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects.

Results: Among 11 PK evaluable patients, encorafenib C_max and AUC_last were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil.

Conclusion: The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment.

Clinical trial registration: ClinicalTrials.gov NCT03864042, registered 6 March 2019.

Keywords: Drug-drug interaction; Modafinil; Oncology.

Fig. 1

Study design Abbreviations: PK = pharmacokinetics

Fig. 2

Mean (+ SD) Plasma Concentration-Time Profiles for Encorafenib and LHY746 by Study Day. The solid lines represent the data on Day 14 after encorafenib 450 mg QD and binimetinib 45 mg BID coadministration and the dotted lines represent the data on Day 21 after modafinil coadministration, 400 mg QD, beginning on Day 15 and extending through Day 21. The solid dots represent the mean analyte concentration at the time point specified. The black lines represent the upper standard deviation of the analyte concentration at each time point. Figure 2A presents encorafenib concentrations and Fig. 2B presents LHY746 concentrations

Fig. 3

Effect of Steady-State Modafinil on Steady-state Encorafenib and LHY746 PK Parameters. Participants were administered 450 mg QD encorafenib and 45 mg BID binimetinib from Day 1 to the end of the study and 400 mg QD modafinil was coadministered from Day 15–21. AUC_last, area under the curve from 0 to the last measurable point; CI, confidence interval; C_max, maximum observed concentration; GMR, geometric mean ratio

Fig. 4

Mean (+ SD) Concentration-Time Profiles for Plasma Binimetinib and AR00426032 by Study Day. The solid lines represent the data on Day 14 and the dotted lines represent the data on Day 21. The solid dots represent the mean plasma concentrations at the time point specified. The black lines represent the upper standard deviation of the plasma concentrations at each time point. Figure 4A presents binimetinb concentrations and Fig. 4B presents AR00426032 concentrations

Fig. 5

Effect of Steady-State Modafinil on Steady-state Binimetinib and AR00426032 PK Parameters. Participants were administered 450 mg QD encorafenib and 45 mg binimetinib from Day 1 to the end of the study and 400 mg QD modafinil was coadministered from Day 15-21. AUC_last, area under the curve from 0 to the last measurable point; CI, confidence interval; C_max, maximum observed concentration; GMR, geometric mean ratio