Ribociclib is not a substrate or inhibitor of Oatp1b-mediated uptake in vivo.

[PURPOSE] Ribociclib is a CDK4/6 inhibitor used to treat HR+/HER2- breast cancer. Despite regulatory documents suggesting that ribociclib may inhibit both CYP3A and OATP1B-type transport in vitro, it is unclear whether CDK4/6 inhibitors interact with these mechanisms in vivo. Based on two cases of severe rhabdomyolysis in patients taking a CDK4/6 inhibitor and simvastatin, a CYP3A and OATP1B substrate, we tested the hypothesis that CDK4/6 inhibitors may precipitate drug-drug interactions through these mechanisms.

[METHODS] We assessed the ability of CDK4/6 inhibitors to inhibit CYP3A and OATP1B-type transporters. Based on these data, we performed pharmacokinetic studies and toxicity assessments to determine whether ribociclib is a substrate or inhibitor of OATP1B-type transport in vivo.

[RESULTS] Ribociclib inhibited the metabolism of triazolam, a CYP3A probe, in vivo. Additionally, CDK4/6 inhibitors inhibited OATP1B-type transporters in vitro. However, ribociclib, the most potent OATP1B inhibitor, did not influence the pharmacokinetics or pharmacodynamics of the OATP1B substrates CDCA-24G or paclitaxel. Furthermore, Oatp1b2 deficiency did not alter the pharmacokinetics of ribociclib.

[CONCLUSION] Our findings suggest that clinically significant OATP1B-mediated interactions are not anticipated with CDK4/6 inhibitors, either as victims or perpetrators, which supports ongoing clinical trials investigating the co-administration of CDK4/6 inhibitors with OATP1B substrates and inhibitors.