127: Phase I Open Label Study to Evaluate the Effects of Strong CYP1A2 Inhibitor on Savolitinib Pharmacokinetics in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: Savolitinib is a potent and selective small molecule hepatocyte growth factor receptor (MET) kinase inhibitor. Based on in-vitro liver microsomes and S9 fractions studies, savolitinib is metabolized by several metabolic enzymes, including both CYP450 enzymes (mainly CYP1A2 and minor contribution from CYP3A4) and non-CYP enzymes (aldehyde oxidase, UDP-glucuronosyltransferases). The formation of savolitinib metabolites M2 and M3 is mediated by CYP1A2 (minor contribution from CYP2C19 and CYP2D6) and non-CYP pathway, respectively. This study was conducted to quantify the magnitude of the effect of fluvoxamine (strong CYP1A2 inhibitor) on the pharmacokinetics of savolitinib.

Description of Methods & Materials: This was a Phase I, open-label, fixed-sequence, 2-treatment period study to assess the effect of strong CYP1A2 inhibitor (fluvoxamine) on savolitinib exposure in healthy male subjects (n=16). Following full written informed consent, subjects were screened for eligibility and enrolled into the study within 28 days of visit 1. Following overnight fasting ( > 10 hours), on the morning of visit 2 Day 1 subjects received a single oral dose of 300 mg of savolitinib and serial PK samples were collected until 72 hours post-dose. Following a washout period of 10 days, subjects received fluvoxamine 50 mg BID for 4 days, on day 5 savolitinib (300 mg) was co-administered with fluvoxamine and fluvoxamine dosing was continued until the last PK sample collection at 72 hours post-dose.

Data & Results: The geometric mean ratios (90% CIs) of Cmax, AUClast and AUCinf for savolitinib in combination with fluvoxamine compared to savolitinib alone were 1.953 (1.672, 2.282), 3.229 (2.847, 3.664) and 3.246 (2.867, 3.675), respectively. The geometric mean ratios (90% CIs) of Cmax, AUClast and AUCinf for M2 when savolitinib was dosed in combination with fluvoxamine compared to savolitinib alone were 0.1201 (0.104, 0.139), 0.349 (0.314, 0.386) and 0.367 (0.332, 0.405), respectively (table 1). The metabolite-to-parent ratios for M2 were lower when savolitinib was dosed in combination with fluvoxamine compared to savolitinib alone, suggesting reduced CYP1A2 activity. The geometric mean ratios (90% CIs) of Cmax, AUClast and AUCinf for M3 when savolitinib was dosed in combination with fluvoxamine compared to savolitinib alone were 1.575 (1.366, 1.816), 3.194 (2.787, 3.661) and 3.265 (2.852, 3.738), respectively. However, the metabolite-to-parent ratios for M3 were similar when savolitinib was dosed in combination with fluvoxamine compared to savolitinib alone, suggesting no change in the non-CYP pathway activity. No additional new safety finding was observed in this study.

Interpretation, Conclusion or Significance: Co-administration of savolitinib with strong CYP1A2 inhibitor increases the exposure of savolitinib by more than 3 fold, suggesting a moderate drug-drug interaction.

Disclosures: Kowser Miah, Jitendar Reddy, Pradeep Sharma, Ike Igwegbe, Simon Nelson, Caitlin Muldoon, and Karthick Vishwanathan: Authors are employee of AstraZeneca and own stock in the company. Ronald Goldwater is an employee of Parexel.

Citations/References:

Additional Information/Authors: NA