EFFECTS OF ITRACONAZOLE AND CARBAMAZEPINE ON THE PHARMACOKINETICS OF REMLIFANSERIN (ACP-204) IN HEALTHY ADULTS

Background

Remlifanserin is a potent serotonin 2A (5-HT2A) receptor inverse agonist/antagonist under investigation for the treatment of Alzheimer’s disease psychosis and Lewy body dementia psychosis. In vitro data indicate that oxidative metabolism of remlifanserin is predominantly driven by cytochrome P450 (CYP) 3A4. Separate studies were conducted to elucidate the effects of the strong CYP3A4 inhibitor, itraconazole (ITR), and the strong CYP3A4 inducer, carbamazepine (CAR), on the pharmacokinetics of remlifanserin.

Methods

The pharmacokinetics of a single oral dose of remlifanserin in the absence or presence of multiple oral doses of ITR or CAR were assessed in two phase 1, open-label, fixed-sequence, 3-period drug-drug interaction studies in healthy adults. In the ITR study, treatment periods included: remlifanserin 30 mg alone (Treatment Period 1), multiple doses of ITR 200 mg alone (Treatment Period 2), and remlifanserin 30 mg + ITR 200 mg (Treatment Period 3). In the CAR study, treatment periods included: remlifanserin 90 mg alone (Treatment Period 1), multiple escalating doses of CAR up to 300 mg twice daily alone (Treatment Period 2), and remlifanserin 90 mg + CAR 300 mg twice daily (Treatment Period 3). For both studies, log-transformed pharmacokinetic parameters (maximum measured plasma concentration [Cmax] and areas under the plasma concentration-time curve from time 0 to infinity [AUC0-∞] and to the last quantifiable time point [AUC0-t]) were analyzed using a mixed-effects model with treatment period as a fixed effect and participant as a random effect. Treatment Period 3 (remlifanserin + ITR or CAR, test group) was compared with Treatment Period 1 (remlifanserin alone, reference group) using geometric least squares mean ratios (%) and corresponding 90% confidence intervals (CIs). Additionally, differences in time to maximum plasma concentration (Tmax) were analyzed using the exact Wilcoxon rank sum test. Safety endpoints (ie, treatment-emergent adverse events [TEAEs], clinically significant findings on physical examination, vital signs, laboratory tests, and electrocardiogram [ECG] parameters) were assessed across all periods.

Results

A total of 17 participants were included in the pharmacokinetic analysis set for the ITR study, and 16 for the CAR study. Upon coadministration with ITR, the Cmax of remlifanserin increased to 138% (90% CI: 130% - 147%), and the extent of exposure increased 3-fold compared to remlifanserin administered alone (AUC0-∞: 335% [90% CI: 301% - 374%]; AUC0-t: 312% [90% CI: 275% - 354%]). Upon coadministration with CAR, the Cmax of remlifanserin was reduced to 48% (90% CI: 43% - 54%), and both AUC0-∞ and AUC0-t values were reduced to 33% (90% CI: 29% - 37%), without impact to Tmax (median difference: 0; p-value: 0.83). No serious TEAEs or clinically meaningful changes in physical examination, vital signs, laboratory tests, or ECG results were reported in either study.

Conclusions

Administration of remlifanserin in the presence of the strong CYP3A4 inhibitor, ITR, markedly increased remlifanserin systemic exposure, whereas coadministration with the strong CYP3A4 inducer, CAR, reduced remlifanserin systemic exposure. Coadministration of remlifanserin with ITR or CAR was safe and generally welltolerated.