Ribociclib, sold under the brand nameKisqali, is an inhibitor of cyclin D1/CDK4 and CDK6, and is used for the treatment of certain kinds of breast cancer. It is also being studied as a treatment for other drug-resistant cancers. It was developed by Novartis and Astex Pharmaceuticals.
As ribociclib is mainly metabolized by the liver enzymeCYP3A4, inhibitors of this enzyme increase its concentrations in the body and could potentiate side effects and toxicity. Examples of such inhibitors include ketoconazole and similar antifungal drugs, ritonavir, clarithromycin, as well as grapefruit. Conversely, drugs that induce CYP3A4, such as rifampicin and St John's Wort, can decrease ribociclib concentrations. Ribociclib itself is a moderate to strong CYP3A4 inhibitor and therefore can increase concentrations of other drugs that share this metabolism, as has been shown with midazolam. It also inhibits a number of transporter proteins and could thus theoretically interfere with the transport of other drugs in the body. It could also amplify QT prolongation of other drugs such as antiarrhythmics, clarithromycin, and haloperidol.
Pharmacology
Mechanism of action
s 4 and 6 are enzymes that have been shown to promote cell division and multiplication in both normal and cancer cells. Many cancer cells have shown abnormalities that increase the activity of CDK, leading to the inactivation of certain tumor suppressor genes. When used in combination with other drugs such as an ALK or an MEK inhibitor, ribociclib has been shown to have a synergistic effect, resulting in improved responses. Again, this is likely a result of "crosstalk" between signaling pathways. Simply blocking one pathway in cancer tumorigenesis can sometimes result in "tumor compensation", where the tumor compensates for the blocked signaling pathway by utilizing other pathways to survive. By blocking several pathways at once, it is thought that the tumor is less able to compensate, and a greater anti-tumor response is often observed. Utilizing ribociclib in combination with other agents has been shown to reduce the development of resistance to these agents. In other words, cancer’s development of drug resistance can be mitigated with the addition of ribociclib to the therapeutic regime.
Pharmacokinetics
The percentage of ribociclib absorbed in the gut has not been determined. Highest blood plasma levels are reached after one to four hours; and after repeated dosage, steady state concentrations are reached after about eight days. Food intake has no effect on absorption rates. When in the bloodstream, about 70% of ribociclib are bound to plasma proteins. The substance is mainly metabolized by CYP3A4 and subsequently by various phase II enzymes, resulting in a large number of metabolites. Those with highest blood plasma concentrations in humans are called CCI284, LEQ803 and M1. All metabolites have negligible clinical activity. Ribociclib has a slight tendency to accumulate in the body. It is eliminated with an average biological half-life of 32 hours, mostly via the feces, but also via the urine. The unchanged drug accounts for 17% of the substance in the feces and 12% of the substance in the urine, the rest being metabolites.
