RIBOCICLIB SUCCINATE

Product Description

Medical uses

Ribociclib Succinate was approved by the U.S. Food and Drug Administration(FDA) in March 2017, and theEuropean Medicines Agency(EMA) in August 2017, for use in combination with anaromatase inhibitor(such asletrozole) to treatHR-positive,HER2-negativeadvanced ormetastatic breast cancers. In theclinical trialrelevant for the drug’s approval, ribociclib significantly improvedprogression-free survival (PFS), that is, the time span the cancer did not get worse.

Side effects

The most common side effects in studies were decreasedblood cellcounts, mainlyneutropenia(in 75% of patients, as compared to 5% under placebo), but alsoanemia(18% vs. 5%). Gastrointestinal disorders were also common, for examplenausea(52% vs. 29%) and diarrhea (35% vs. 22%), as wasalopecia(33% vs. 16%). The drug alsoincreases the QT intervaland liver enzymes (alanine transaminase,aspartate transaminase).

Interactions

As ribociclib succinate is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme increase its concentrations in the body and could potentiate side effects and toxicity. Examples of such inhibitors includeketoconazoleand similar antifungal drugs,ritonavir,clarithromycin, as well asgrapefruit. Conversely, drugs that induce CYP3A4, such asrifampicinandSt 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 withmidazolam. It also inhibits a number oftransporter proteinsand could thus theoretically interfere with the transport of other drugs in the body. It could also amplify QT prolongation of other drugs such asantiarrhythmics, clarithromycin, andhaloperidol.

Pharmacokinetics

The percentage of ribociclib succinate absorbed in the gut has not been determined. Highest blood plasmalevels 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 toplasma proteins. The substance is mainly metabolized by CYP3A4 and subsequently by variousphase II enzymes, resulting in a large number of metabolites. Those with highest blood plasma concentrations in humans are called CCI284 (an unspecifiedN-hydroxylationproduct), LEQ803 (theN-demethylationproduct) and M1 (aglucuronide). All metabolites have negligible clinical activity. Ribociclib succinate has a slight tendency to accumulatein the body. It is eliminated with an averagebiological half-life of 32 hours, mostly (69%) via the feces, but also (23%) 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 (source Wikipedia).  

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