Evaluation of gastric pH-dependent drug interaction between famitinib
and the commonly used proton pump inhibitor omeprazole in healthy
subjects
Linlin Hu1,2, Mingmin Cai2, Wei
Qian2, Ting Dou2, Qiuyue
Sun2, Lu Tang2, Huiping
Wang1,2
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