Mechanistic insights into pharmacokinetic interactions between simvastatin and vismodegib: Implications for...

Aberrant Sonic Hedgehog (Shh) pathway activation drives medulloblastoma pathogenesis. As previously shown, the smoothened antagonist vismodegib and cholesterol synthesis inhibitor simvastatin exhibit synergistic growth inhibition against subcutaneous medulloblastoma allografts in SCID mice. Critically, at the tested dose, simvastatin alone showed no significant bone developmental toxicity. This suggests that the combination may reduce vismodegib dosage and mitigate its associated skeletal developmental toxicity. To elucidate pharmacokinetic mechanisms underlying this synergy, we investigated vismodegib-simvastatin interactions. Mice received oral single-dose vismodegib, simvastatin, or their co-administration for pharmacokinetic profiling. In vitro assessments included the effects of vismodegib on organic anion transporting polypeptide 1B1 (OATP1B1) (using HepG2 and CHO-OATP1B1 cells) and cytochrome P450 (CYP) enzymes (using mouse liver microsomes and molecular docking). Co-administration significantly increased the systemic exposure of simvastatin and simvastatin acid, reflected by 1.97-fold and 2.16-fold increases in AUC (P < 0.01), respectively, and reduced their clearance to 42.9 % (P = 0.11) and 53.5 % (P < 0.05) relative to simvastatin alone. Enhanced tissue (brain/cartilage) exposure of simvastatin and simvastatin acid was also observed. In vitro, vismodegib (1) significantly inhibited OATP1B1 transport function (IC₅₀: 2.0 ± 0.3 μM; determined with the model substrate 2',7'-dichlorofluorescein (DCF)); (2) concentration-dependently downregulated SLCO1B1 (encoding OATP1B1) transcription in HepG2 cells; and (3) competitively inhibited CYP3A4-mediated simvastatin acid metabolism (IC₅₀: 15.8 ± 3.3 μM); (4) is predicted to inhibit CYP3A4 and OATP1B1 via steric hindrance, as revealed by molecular docking analysis. This study provides the novel mechanistic insights of vismodegib-simvastatin pharmacokinetic synergy through dual OATP1B1/CYP3A4 inhibition. Taken together, these findings establish a mechanistic foundation for a proposed therapeutic optimization strategy: Reducing vismodegib dosing while leveraging its inhibition-driven elevation of simvastatin systemic/tissue exposure, thereby mitigating dose-limiting skeletal toxicity while maintaining anti-tumor efficacy. This mechanism-based strategy provides a clinically actionable framework for pediatric medulloblastoma with urgent unmet therapeutic needs.