Annex 1. The abemaciclib metabolic pathway and its interplay with the membrane transporters: Understanding drug-drug interactions (DDIs).


Abemaciclib is the third selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6i) approved for the treatment of patients with locally advanced or metastatic breast cancer, hormone receptor positive and human epidermal growth factor receptor 2 negative, in combination with either an aromatase inhibitor or fulvestrant.

In order to understand the drug-drug interactions (DDIs) between abemaciclib and the concomitant medication prescribed to a specific patient, we briefly describe below the pharmacokinetic profile of abemaciclib (absorption, distribution, metabolism and elimination) and its interplay with the membrane transporters. By adding this annex, we provide information, at least as metabolism is concerned, on the three CDK4/6i approved (for ribociclib and palbociclib metabolism see section “Drug metabolic pathways and membrane transporters: how to interpret DDIs with palbociclib and ribociclib?” of our previous article here). As mentioned previously (see Section "Aims of the Platform"), abemaciclib data was not included in the manuscript that gave rise to this website, since that publication was focused only on the two CDK4/6 approved in Spain by that time (palbociclib and ribociclib).

Abemaciclib metabolic pathway

Absorption. Abemaciclib can be taken with or without food and has a high solubility. Therefore, no interaction of abemaciclib with proton pump inhibitors, H2- receptor antagonists or antacids are expected.

Distribution. . Abemaciclib is highly bound to plasma proteins (96% -98%).

Metabolism. Abemaciclib is mainly metabolized by the cytochrome P-450 pathway, specifically CYP3A4, which leads to the formation of three active metabolites (LSN2839567, LSN3106726 and LSN3106729). Both abemaciclib and its metabolites are major substrates of CYP3A4. Hence, concomitant administration with CYP3A4 inhibitor or inductor drugs may results in DDI.

Co-administration with strong CYP3A4 inhibitors may lead to the accumulation of abemaciclib and, accordingly, an increase in its toxicity. So, the combination of abemaciclib with strong CYP3A4 inhibitors should be avoided. If this is not possible, the dose of abemaciclib should be reduced to 100 mg twice daily and for patients who are already taking 100 mg twice daily, a further reduction to 50 mg twice daily should be necessary. For patients on 50 mg twice daily, either a close monitoring, a reduction to 50 mg once a day or a discontinuation of abemaciclib therapy should be considered. The dose of abemaciclib should be increased again, or re-started, whatever applies once the concomitant treatment with the strong CYP3A4 inhibitor has finished and 5 half-lives of this drug have passed. Co-administration with moderate or weak inhibitors should also be used with caution.

Conversely, concomitant administration with drugs that are CYP3A4 inducers can decrease the concentration of abemaciclib and, in consequence, may result in loss of efficacy. In this case the combination should be avoided, and alternative drugs should be strongly considered.

Finally, and unlike palbociclib and ribociclib, abemaciclib has no effect in CYP3A4 metabolism; in other words, it is neither an inhibitor nor an inducer of this enzymatic complex.

Interplay of abemaciclib and the membrane transporters

The interplay of abemaciclib and the membrane transporters is bi-directional, so we distinguish the effect of membrane transporters on abemaciclib, and, reciprocally, the impact of abemaciclib on the membrane transporters.

Effect of membrane transporters on abemaciclib and its metabolites:

The in vitro results indicate that abemaciclib is a substrate of P-glycoprotein (gp-P) and Breast Cancer Receptor Protein (BCRP). However, no impact of gp-P or BCRP on either absorption or distribution of abemaciclib has been observed in vivo. Therefore, there is a low probability of DDIs when it is administered with inhibitors or inducers of gp-P or BCRP.

Conversely, and also according to in vitro experiments, abemaciclib is not a substrate of either the hepatic uptake transporters OATP1B1, OATP1B3 (organic anion transporters) or the renal transporter OCT1 (organic cationic transporter 1).

Effect of abemaciclib and its metabolites on membrane transporters:

In vitro data has shown that abemaciclib is an inhibitor of gp-P, BCRP and OCT1. Hence, caution should be exercised when abemaciclib is co-administred with drugs that are substrates of these transporters, as it may increase the concentration of these latter drugs and, in consequence, their toxicity.

Similarly, abemaciclib and its metabolites have demonstrated to inhibit the renal trasporters OCT2 (organic cationic transporter 2), multidrug and toxin extrusion protein MATE 1 and MATE2-K. Thus, caution should be taken when abemaciclib is administered with drugs known to be substrates of these renal transporters.

Abemaciclib has also proven to inhibit organic anion transporters OAT1 and OATP3 in vitro. No impact of this inhibition at the clinical level has been observed so far. However, caution should be exercised with drugs that are substrates of these transporters until more evidence is available.

Finally, abemaciclib and its metabolites has not demonstrated to inhibit the hepatic trasporters OATP1B1 and OATP1B3 in vitro.


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