Evaluation of gastric pH-dependent drug interaction between famitinib and the commonly used proton pump inhibitor omeprazole in healthy subjects

Linlin Hu^1,2, Mingmin Cai², Wei Qian², Ting Dou², Qiuyue Sun², Lu Tang², Huiping Wang^1,2

¹Office of clinical trial institution, Nanjing Zhongda Hospital, Southeast University, School of Medicine, Nanjing, 210009, China.

²Department of Phase I Clinical Trial Unit, Nanjing Zhongda Hospital, Southeast University, School of Medicine, Nanjing, 210009, China.

Correspondence

Linlin Hu and Huiping Wang, Office of clinical trial institution, Department of Phase I Clinical Trial Unit, Nanjing Zhongda Hospital, Southeast University, School of Medicine, Nanjing, 210009, China.

Email: eliza50@sina.com, Email:369594546@qq.com

What is already known about this subject?

1. Absorption of an orally administered drug with pH-dependent solubility may be altered when it is co-administered with a gastric acid reducing agent (ARA).

2. Famitinib is a multi-targeted tyrosine kinase receptor inhibitor which is effective in a wide variety of solid and hematologic malignancies.

3. Famitinib is a BCS class IV drug, exhibiting pH-dependent solubility.

What this study adds

1. The proton pump inhibitor omeprazole does not have large effects on the PK behavior of famitinib and its metabolite SHR116637.

2. The safety profile was generally good upon coadministration.

3. Prescribers and patients may not have to be concerned about altered effectiveness or safety when using famitinib with ARAs.

Abstract

Aims: To evaluate the potential gastric pH-dependent drug-drug interaction (DDI), safety and tolerability of famitinib co-administered with omeprazole in healthy subjects.

Methods: Twenty healthy subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Famitinib was administered as a single oral 25 mg under a fasting condition on day 1, omeprazole (40 mg once daily) was given on days 10–14, concomitantly with famitinib on day 15, and for the follow-up 7 additional days (days 16–22). Blood samples were collected for the pharmacokinetic analysis of both famitinib and its metabolite SHR116637 following each famitinib dose. Safety and tolerability were assessed during the whole progress via clinical laboratory tests.

Results: The least-squares geometric mean ratios (GMRs) (90% CI) ofC _max, AUC _0-t andAUC _0-∞ for famitinib combined with omeprazole to famitinib alone were 0.989 (0.953, 1.027), 0.956 (0.907, 1.007) and 0.953(0.905, 1.005) respectively. For the metabolite SHR116637, their GMRs (90% CI) of the above parameters were 0.851 (0.786, 0.920), 0.890 (0.838, 0.946）and 0.887 (0.835, 0.943), indicating the absence of significant differences in the parameters respectively. During the treatment period, 9(45%) subjects reported 16 treatment emergent adverse events (TEAE), among which 6 subjects (30%) reported 9 TEAEs and 1 subject (5%) reported 1 TEAE during famitinib or omeprazole administered alone respectively, 5 subjects (25.0 %) reported 6 TEAEs during in the combined administration phase.

Conclusion: Omeprazole did not have a significant influence on the pharmacokinetics (PK) of famitinib and SHR116637, and the safety profile was good upon co-administration.

Keywords

Gastric pH-dependent drug interactions, omeprazole, pharmacokinetics, famitinib