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

Area of Science:

• Pharmacology
• Oncology
• Drug Metabolism

Background:

• Ribociclib is a CDK4/6 inhibitor for HR+/HER2- breast cancer.
• Regulatory documents suggest potential in vitro inhibition of CYP3A and OATP1B by ribociclib.
• Clinical cases of rhabdomyolysis with CDK4/6 inhibitors and simvastatin prompted investigation into drug-drug interactions.

Purpose of the Study:

• To assess the in vivo interaction potential of CDK4/6 inhibitors with CYP3A and OATP1B mechanisms.
• To test the hypothesis that CDK4/6 inhibitors may cause drug-drug interactions via CYP3A and OATP1B pathways.
• To determine if ribociclib acts as a substrate or inhibitor of OATP1B in vivo.

Main Methods:

• Assessed CDK4/6 inhibitor ability to inhibit CYP3A and OATP1B transporters in vitro.
• Conducted pharmacokinetic studies and toxicity assessments for ribociclib and OATP1B substrates.
• Utilized triazolam as a CYP3A probe and CDCA-24G/paclitaxel as OATP1B substrates in vivo.

Main Results:

• Ribociclib inhibited CYP3A probe metabolism in vivo.
• CDK4/6 inhibitors demonstrated in vitro inhibition of OATP1B transporters.
• Ribociclib did not affect the pharmacokinetics or pharmacodynamics of OATP1B substrates, despite being a potent OATP1B inhibitor.
• Oatp1b2 deficiency did not alter ribociclib pharmacokinetics.

Conclusions:

• Clinically significant OATP1B-mediated drug interactions are unlikely with CDK4/6 inhibitors.
• CDK4/6 inhibitors are neither significant victims nor perpetrators of OATP1B interactions.
• Findings support ongoing clinical trials for co-administering CDK4/6 inhibitors with OATP1B substrates/inhibitors.