026: Phase I Open Label Study to Evaluate the Effects of Savolitinib on the Pharmacokinetics of P-gp, OATP1B1/3, OCT2, MATE1/2K & OAT1/3 Substrates in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: Savolitinib is a potent and selective small molecule hepatocyte growth factor receptor (MET) kinase inhibitor. In vitro, savolitinib is a substrate of P-gp and weak inhibitor. Additionally, based on in-vitro data, savolitinib is an inhibitor of OCT2, OATP1B1, and OATP1B3, and clinically significant DDI cannot be ruled out when co-administered with the substrates of these transporters. Moreover, based on in-vitro data savolitinib and its metabolite M2 may also inhibit MATE1/2K and OAT1/3 leading to an increased chance of a clinically relevant DDI between savolitinib and any co-administered drug that is a substrate for these transporters. This study was conducted to evaluate clinical DDI between savolitinib and the substrates of the transporters mentioned above.

Description of Methods & Materials: This study was a Phase I, fixed-sequence, open-label, 2 period study to assess the effects of savolitinib on the pharmacokinetics (PK) of substrates of human transporters digoxin (P-gp), rosuvastatin (OATP1B1/3), metformin (OCT2, MATE1/2K), and furosemide (OAT1/3) in healthy male subjects (n=23). Following full written informed consent, subjects were screened for eligibility and enrolled into the study within 28 days of visit 1. Each subject received a single dose of a drug cocktail of 4 medications (0.25 mg digoxin, 5 mg furosemide, 500 mg metformin hydrochloride, and 10 mg rosuvastatin) on Day 1 of period 1. Subjects had a washout period of at least 14 days between period 1 and period 2. On Day 1 of period 2, subjects received savolitinib (600 mg) in combination with the drug cocktail of 4 medications as administered in Period 1. Serial PK samples were collected at both period 1 and period 2.

Data & Results: The geometric mean AUCinf, AUClast, and AUC(0-24h) of digoxin were comparable between periods, whereas the Cmax was 23% higher in period 2 compared to period 1. Geometric mean systemic exposure (AUCinf, AUClast, AUC(0-24h), and Cmax) of metformin in period 2 were higher than in period 1, with AUCinf and AUClast both increased by 43%, while AUC(0-24h) and Cmax increased by 44% and 58%, respectively. Geometric mean systemic exposure (AUCinf, AUClast, AUC(0-24h), and Cmax) of rosuvastatin in period 2 were slightly higher than in period 1, with AUCinf increased by 25%, AUClast increased by 26%, AUC(0-24h) increased by 27%, and Cmax increased by 30%, respectively. Furosemide systemic exposure (geometric mean AUCinf, AUClast, AUC(0-24h), and Cmax) were comparable between periods, with the largest change observed being in the AUCinf, AUClast, and AUC(0-24h) (4% larger in period 2) (table 1). Metformin renal clearance and Fe(0-48h) in period 2 were 41% and 13% lower than in period 1 which may be due to savolitinib-mediated weak inhibition of MATE1/2K and/or OCT2 transporters.

Interpretation, Conclusion or Significance: Systemic exposure of digoxin, rosuvastatin, and furosemide following administration with savolitinib were comparable to when dosed alone, suggesting savolitinib does not inhibit P-gp, OATP1B1/3, or OAT1/3 transporters to a clinically significant level. Whereas savolitinib appeared to be weak inhibitor of MATE1/2K and/or OCT2 in the clinic.

Disclosures: Kowser Miah, Deeyen Karsanji, Carlos Silva, Ike Igwegbe, Simon Nelson, Caitlin Muldoon, Karthick Vishwanathan: Authors are employee of AstraZeneca and own stocks in the company. Thomas Koernicke is an employee of Parexel.

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