评估CYP1A2抑制对Savolitinib药代动力学影响的1期开放标签研究

Savolitinib is an oral, potent, selective CNS-penetrant MET-tyrosine kinase inhibitor that in vitro studies indicate is metabolized by cytochrome P450 (CYP) enzymes, including CYP1A2, and by non-CYP enzymes, such as aldehyde oxidase (AO). Savolitinib primary metabolites, M2 and M3, are formed mainly by CYP1A2 and AO, respectively. This Phase 1, open-label study evaluated the impact of CYP1A2 inhibition by fluvoxamine on the pharmacokinetics of savolitinib and its metabolites in 16 healthy male volunteers. Volunteers received a single oral dose of 300 mg savolitinib and, following a ≥ 10-day washout period, 50 mg twice-daily oral fluvoxamine for 6 days, with a single oral dose of 300 mg savolitinib co-administered on Day 5. Serial pharmacokinetic samples were collected during both study periods. Savolitinib, M2, and M3 were measured using high-performance liquid chromatography with tandem mass spectrometry. Systemic exposure of savolitinib increased by approximately 2-fold (maximum plasma concentration) and 3-fold (area under the plasma concentration-time curve from time 0 to infinity) when savolitinib was administered with fluvoxamine compared with savolitinib alone. Systemic exposure of M2 and M3 decreased and increased, respectively, when savolitinib was administered with vs. without fluvoxamine, while the ratio of M2/savolitinib was reduced and that of M3/savolitinib remained unchanged. These data suggest a significant drug-drug interaction between savolitinib and the strong CYP1A2 inhibitor, fluvoxamine, and that CYP1A2 is involved in the formation of M2, but not M3. No new safety concerns were observed when savolitinib was administered alone or with twice-daily fluvoxamine.