Effect of ripretinib on the pharmacokinetics (PK) of repaglinide, a sensitive CYP2C8 probe substrate, in adult patients (pts) with advanced gastrointestinal stromal tumor (GIST).

Abstract

e23511 Background: Ripretinib is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of adult pts with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite, DP-5439, inhibited CYP2C8 in vitro and met the criteria for a clinical assessment. This open-label study evaluated the effect of ripretinib on the PK of repaglinide, a sensitive CYP2C8 probe substrate, in pts with advanced GIST who progressed on or had intolerance to 2 or more prior TKI therapies. Methods: A single oral 0.5-mg repaglinide dose was administered on cycle 1 day 1 (C1D1) to 13 pts in a fasted state (no food or drink except water for ≥6 hours predose). Ripretinib 150 mg once daily was administered beginning on C1D2. On C1D15, a single 0.5-mg repaglinide dose was coadministered with ripretinib. Ripretinib was continued until disease progression, unacceptable toxicity, or withdrawal of consent. PK samples were collected predose through 24 hours postdose on C1D1 and C1D15 and analyzed for repaglinide. PK parameters were calculated using noncompartmental analysis; ln-transformed PK parameters for repaglinide were compared using ANOVA with treatment (with ripretinib vs alone) as a fixed effect and pt as a random effect. Geometric mean ratios and 90% confidence intervals (CIs) for maximum concentration (C max ), area under the curve from time 0 to last quantifiable concentration (AUC 0-t ), and AUC extrapolated to infinity (AUC 0-∞ ) were computed. Patient safety was monitored. Results: Of 13 pts, 11 (85%) were PK evaluable. Repaglinide AUC 0-t and AUC 0-∞ increased by 24% and 26%, respectively, with ripretinib vs alone. Repaglinide C max and time to reach maximum concentration were comparable with ripretinib vs alone. All 13 pts (100%) had at least 1 treatment-emergent adverse event (TEAE); 4 pts (31%) had Grade 3 TEAEs, with 2 pts (15%) experiencing serious AEs that were Grade 3 and were not related to study treatment. Conclusions: Ripretinib is a weak inhibitor of CYP2C8, with no impact on absorption and a small, clinically insignificant increase in total repaglinide exposure. The safety profile of ripretinib was consistent with its established use in advanced GIST. This study provides the basis for approved concomitant use of ripretinib with CYP2C8 substrates. Clinical trial information: NCT04530981 . Plasma PK parameters of repaglinide by treatment. Parameter Repaglinide Reference n = 11 Repaglinide + ripretinib Test n = 11 Geometric mean ratios (90% CI) C max , pg/mL 9560 (39.5) 9150 (54.9) 0.96 (0.69–1.32) AUC 0–t , h·pg/mL 16,100 (24.9) 20,000 (32.0) 1.24 (1.05–1.46) AUC 0–∞ , h·pg/mL a 16,300 (26.1) 20,000 (32.6) 1.26 (1.05–1.51) Data presented as geometric mean (% geometric coefficient of variation). a n = 10.