1 Introduction
Multi-kinase inhibitors (MKIs), particularly tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies1-3. The oral administration route of TKIs offers logistic flexibility and is convenient for the patients, however, despite these advantages, it also causes a highly relevant new problem. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility4-6. The poor and variable pH-dependent solubility, together with other variable pharmacokinetic factors, contribute to a significant patient variability in plasma levels and exposure. Next to other factors, TKI therapy is associated with a higher risk for gastrointestinal disorders. A majority of cancer patients frequently take acid–reducing agent (ARA) to alleviate gastroesophageal symptoms, thereby raising the potential for a gastric pH-dependent drug interaction4. This type of DDI may have detrimental effects on the efficacy of TKIs, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including nilotinib or dasatinib4,7,8. Long-term suppression of gastric acidity could decrease the absorption of certain major oral anticancer drugs with pH-dependent solubility and result in subsequent failure of therapy. To address this, guidelines are provided by the FDA and the European Medicines Agency (EMA) that recommend studying the DDI between pH-dependent drugs and ARAs.
Famitinib (famitinib-malate, SHR1020) is a novel and potent multi-targeted receptor TKI that targets at c-kit, vascular endothelial growth factor receptor 2 and 3 (VEGFR-2 and 3), platelet-derived growth factor receptor (PD-GFR), FMS-like tyrosine kinase-3 receptor (FLT3) and protooncogene tyrosine kinase receptor (RET)9,10. Famitinib is a structural analog of sunitinib with improved cell inhibitory activity. Due to its anti-angiogenic effect, it was effective against metastatic renal cell carcinoma, non-small cell lung cancer and metastatic breast cancer11-13. Clinical trials of famitinib in combination with the concurrent medication or chemoradiotherapy also showed its good antitumor abilities against other solid tumors such as metastatic urothelial carcinoma, advanced immunomodulatory triple-negative breast cancer, advanced nasopharyngeal carcinoma, platinum-resistant recurrent ovarian cancer, advanced colorectal cancer and gastric cancer9,14-20. A phase I study showed that famitinib had favorable PK characteristics and was generally well-tolerated. After a single oral administration of famitinib, it was well absorbed and extensively metabolized. The major circulating metabolite SHR116637 was the formation of N-desethyl famitinib, which is pharmacodynamically active but exhibits a lower potency than the parent drug21. Within the dosing range of 4–27 mg, the increase in C maxand AUC 0–24h for famitinib and SHR116637 were proportional to the increase in dose level, T maxof the parent drug and the major metabolite SHR116637 in cancer patients occurred within 3.3–5.3 and 4.0–6.2 h, respectively. The plasma level of SHR116637 is approximately equivalent to 3.6 % of that of the parent drug, and both famitinib and SHR116637 were slowly removed from circulation9. After administration for 28 days, the degrees of famitinib accumulation in vivo were significantly lower than sunitinib and the major side effects were noted in terms of neutrocytopenia, thrombocytopenia, diarrhea, fatigue and peripheral edema, with particularly less severe fatigue and thrombocytopenia9. These toxicities had no significant accumulation while treatment proceeded, however, the common adverse events (AEs) of gastrointestinal reactions, such as nausea and diarrhea, needed ARAs and gastric mucosal protective to alleviate these adverse events.
Although ARAs are extensively used during anticancer treatment, there is still much controversy on how to manage drug–drug interactions (DDIs) between TKIs and ARAs22. Early assessment of pH-dependent DDIs for TKI of poorly soluble and weakly acidic compounds offers various advantages for patient safety. Famitinib has been classified as a BCS class IV drug (low solubility, low permeability) by the FDA. The results of in vitro solubility test showed that the solubility of famitinib was 85, 140 and 8 μg/mL in the medium system of pH 1.0, 4.5, 6.8 respectively. The magnitude of solubility change with increasing pH occurs at a pH of 6.0-6.8. According to the FDA guidance’s decision tree on the evaluation of gastric pH-dependent drug interactions, DDI studies with ARAs are required if the drug dissolution is too low to determine the effect of pH on drug solubility or the solubility of the drug at pH 6.0–6.8 is less than dose divided by 250 mL5. Famitinib fits both of these criteria, so it is necessary to explore the effects of pH on the PK of famitinib, including maximum plasma concentration (C max), area under the curve (AUC), and other PK parameters. Among all therapeutic agents, PPIs are the most prevalent and most potent ARAs and with daily use produce a marked and sustained duration of acid suppression4,5. A prospective study in four French Comprehensive Cancer Centers, more than a quarter of cancer patients used PPIs, mostly on a daily basis and in the long term23. As PPIs generally have a longer duration of suppression effect on gastric acid secretion than H2 blockers and antacids do, they are expected to interfere with the intestinal absorption of TKIs to a greater extent. In this paper, omeprazole, was therefore chosen for the study of famitinib with an ARA. We aim to update the potential gastric pH-dependent drug interactions between omeprazole and famitinib in healthy subjects, as well as to ascertain the safety of co-administration of famitinib and omeprazole.