Based upon the documented relationship of P450 and certain potential drug-drug interactions, this positive data is central to the planned Phase 2 clinical trial where Kevetrin will be used in a combination therapy for the treatment of ovarian cancer.
The testing was performed at the request of the U.S. Food and Drug Administration ("FDA") during Cellceutix’s recent meeting with the FDA pertaining to the planned Phase 2 trial. Per standard protocol, the FDA requires specific studies in an attempt to preempt possible drug interaction complications during human trials.
The requisite in vitro testing met Cellceutix’s expectations in demonstrating that Kevetrin can be combined with another anti-cancer drug without any concerns of adverse drug-drug interactions.
Enzymes produced by cytochrome P450 genes are involved in the synthesis and metabolism of molecules within cells. Cytochrome P450 enzymes (CYP450), found primarily in liver cells, account for 70 to 80% of enzymes involved in drug metabolism (US National Library of Medicine, 2016). There are more than 50 enzymes, but only six metabolize 90% of drugs, especially CYP3A4 and CYP2D6 (Lynch and Price 2007).
Many drugs are metabolized through the CYP450 enzyme system, which can be inhibited or induced by other molecules, such as anti-cancer drugs, grapefruit juice or tobacco. It is important to know if a molecule inhibits or induces these enzymes, especially when used in combination with other drugs, since there is a potential for drug-drug interaction that can cause unexpected adverse events or inactivity (Ogu and Maxa 2000).
Kevetrin, under development as an anti-cancer agent as monotherapy or in combination with chemotherapeutic agents, was assessed for its ability to inhibit or induce P450 enzyme activity.
For assessment of inhibition of CYP450, Kevetrin, at concentrations up to 100 µg/mL, were incubated with human liver microsomes and enzyme-specific substrates at 37°C. The following CYP450 isozymes were evaluated: 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4. Kevetrin showed little to no inhibition and no time dependent inhibition (TDI) effect on any of the seven isozymes tested, whereas the positive controls showed inhibition of the isozymes in the same system, as expected.
For assessment of induction of CYP450, Kevetrin, at 10 and 100 µM, and positive inducers were incubated with primary human liver cells at 37°C for 48 hours. The following CYP450 isozymes were evaluated: 1A2, 2B6, 2C9, 3A4. Enzyme-specific substrates were added, incubated for one hour then metabolites were measured. Kevetrin did not induce any of the four CYP isozymes tested, whereas the positive controls did show induction in the same system, as expected.
Given the lack of inhibition or induction of CYP450, the study met the requirements of the FDA and it is expected that the development of Kevetrin in human clinical trials may proceed in combination with certain other chemotherapeutic agents without concern for potential drug-drug interactions.
Cellceutix is currently finalizing the documentation for submission to the FDA.