A Phase 1 Study to Assess the Effect of Fruquintinib on the Pharmacokinetics of P‐gp and BCRP Substrates in Healthy Subjects

Fruquintinib, a highly selective, oral inhibitor of all three vascular endothelial growth factor receptors (−1, −2, and −3), is approved for previously treated metastatic colorectal cancer. This phase 1, two‐part, two‐period, fixed‐sequence study (NCT05368805) evaluated the potential inhibitory effect of fruquintinib (5 mg) on the pharmacokinetics (PK) of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates. In Part A, 20 healthy subjects received a single oral dose of dabigatran etexilate (P‐gp substrate) 150 mg on Day 1 and Day 5, with fruquintinib co‐administered on Day 5. In Part B, 12 healthy subjects received a single oral dose of rosuvastatin (BCRP substrate) 10 mg on Day 1 and Day 5, with fruquintinib co‐administered on Day 5. Plasma samples were collected to evaluate the PK of dabigatran and rosuvastatin over 96 h, and to measure fruquintinib and its major metabolite M11 concentrations over 192 h. Co‐administration of dabigatran etexilate with fruquintinib resulted in a ~10% decrease in the systemic exposure of dabigatran; geometric mean ratios (GMRs) and 90% CIs were 0.90 (0.66–1.23) for C max and 0.91 (0.68–1.23) for AUC 0–inf . Co‐administration of rosuvastatin with fruquintinib resulted in a decrease in the systemic exposure of rosuvastatin by approximately 16% for C max and 19% for AUC 0–inf ; GMRs and 90% CIs were 0.84 (0.65–1.10) for C max and 0.81 (0.65–1.02) for AUC 0–inf . Fruquintinib had no clinically significant effect on the PK of P‐gp or BCRP substrates, supporting that dose adjustments for substrates of P‐gp or BCRP are unnecessary when co‐administered with fruquintinib.