(P 376) EFFECT OF ITRACONAZOLE (ITZ) AND RABEPRAZOLE (RBP) ON THE PHARMACOKINETICS (PK) OF VIMSELTINIB, AN ORAL INHIBITOR OF THE COLONY-STIMULATING FACTOR 1 RECEPTOR, IN HEALTHY PARTICIPANTS

Objective: Vimseltinib is indicated for treatment of adult patients with symptomatic tenosynovial giant cell tumor for which surgical resection will potentially cause worsening functional limitation or severe morbidity. In preclinical studies, vimseltinib was both a P-gylcoprotein (P-gp) substrate and inhibitor, which may inform drug-drug interactions (DDIs). Here, we report the results of a phase 1, open-label study investigating the effects of ITZ (P-gp inhibitor) and RBP (proton pump inhibitor [PPI] for gastric acid suppression) on the single-dose PK of vimseltinib in healthy participants.

Methods: Adult participants (N = 89) were randomized 1:1:1 to receive a single 30-mg vimseltinib dose on day 1 (arm 1; reference) or 1 h after ITZ/RBP on day 5 (arms 2/3; test). Participants in arm 2 received ITZ 200 mg once daily (QD) on days 1–24 and those in arm 3 received RBP 20 mg QD on days 1–5. Plasma PK samples were collected, and parameters were obtained by noncompartmental analysis. The log-transformed maximum concentration (Cmax), area under the curve (AUC) from first dose to last quantifiable concentration (AUC0–tlast), and AUC extrapolated to infinity (AUC0–inf) of vimseltinib were analyzed using an analysis of variance model. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of Cmax, AUC0–tlast, and AUC0–inf were constructed. Adverse events (AEs) were monitored throughout the study.

Results: Cmax was similar for vimseltinib alone vs with ITZ; the 90% CI for the GMR was within bioequivalence limits (Table). Total vimseltinib exposure (AUC0–tlast and AUC0–inf) was 17% and 22% higher, respectively, with ITZ vs alone. Vimseltinib Cmax, AUC0–tlast, and AUC0–inf was 26%, 25%, and 21% lower, respectively, with RBP vs alone. All treatment-emergent AEs were grade 1/2.

Conclusion: P-gp inhibition with ITZ and gastric acid suppression with RBP had weak effects on total vimseltinib exposure and absorption, respectively. Neither treatment affected the safety profile. Overall, the DDI for vimseltinib with ITZ or with RBP was not considered clinically significant, providing basis for approved concomitant use of vimseltinib with P-gp inhibitors and PPIs.

Plasma PK Parameters of Vimseltinib by Treatment