Effect of ripretinib on the pharmacokinetics (PK) of midazolam (MDZ), a sensitive CYP3A probe substrate, in adult patients (pts) with advanced gastrointestinal stromal tumor (GIST).

Abstract

e23509 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/or DP-5439 (active metabolite) showed weak time-dependent inhibition and weak induction of CYP3A in vitro. MDZ is metabolized by CYP3A in the gut and liver to 1′-hydroxy-midazolam (1′-OH MDZ), making it an ideal probe substrate for CYP3A activity. This open-label study evaluated the effect of ripretinib on the PK of MDZ in pts with advanced GIST who progressed on or had intolerance to 3 or more prior TKI therapies. Methods: A single oral 2-mg MDZ dose was administered on cycle 1 day 1 (C1D1) to 18 pts in a fasted state. Ripretinib 150 mg once daily was administered beginning on C1D3. On C1D12, a single 2-mg MDZ dose was coadministered with ripretinib. Ripretinib was continued until disease progression, unacceptable toxicity, or withdrawal of consent. PK samples were collected predose through 48 hours postdose on C1D1 and C1D12 and analyzed for MDZ and 1′-OH MDZ. PK parameters were calculated using noncompartmental analysis; ln-transformed PK parameters for MDZ and 1′-OH MDZ 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 18 pts, 16 (89%) were PK evaluable. MDZ and 1’-OH MDZ C max , AUC 0-t , and AUC 0-∞ were similar with ripretinib vs alone; 90% CIs were within bioequivalence limits. Time to reach C max , half-life, and metabolite ratios were generally unchanged. All 18 pts (100%) had at least 1 treatment-emergent adverse event (TEAE); 3 pts (17%) had grade 3/4 TEAEs, of which 1 pt (6%) had a fatal outcome (disease progression). All the AEs were unrelated to study treatment. Conclusions: Ripretinib did not alter the PK of MDZ. Therefore, ripretinib is not a clinically relevant CYP3A modulator. Ripretinib exhibited a manageable safety profile consistent with its established use in advanced GIST. Clinical trial information: 2022-501477-40-00. Plasma PK parameters of MDZ and 1’-OH MDZ. Parameter MDZ Reference n = 16 MDZ + ripretinib Test n = 16 Geometric mean ratios (90% CI) MDZ C max , ng/mL 15.5 (32.4) 17.7 (32.7) 1.14 (1.04, 1.25) AUC 0–t , h·ng/mL 39.8 (65.9) 43.9 (39.6) 1.10 (0.969, 1.25) AUC 0–∞ , h·ng/mL 43.6 (62.8) 46.9 (38.0) 1.08 (0.950, 1.22) 1’-OH MDZ C max , ng/mL 4.87 (47.1) 5.34 (41.5) 1.10 (1.00, 1.20) AUC 0–t , h·ng/mL 11.0 (42.7) 11.4 (37.3) 1.03 (0.909, 1.17) AUC 0–∞ , h·ng/mL 12.1 (47.5) a 12.6 (36.5) b 1.07 (0.918, 1.24) Data presented as geometric mean (% geometric coefficient of variation) unless otherwise noted. a n = 13. b n = 15.