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Purpose <p>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 <i>in vitro</i>, it is unclear whether CDK4/6 inhibitors interact with these mechanisms <i>in vivo</i>. 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.</p> Methods <p>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 <i>in vivo.</i></p> Results <p>Ribociclib inhibited the metabolism of triazolam, a CYP3A probe, <i>in vivo</i>. Additionally, CDK4/6 inhibitors inhibited OATP1B-type transporters <i>in vitro</i>. 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月7日

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  • Thomas Drabison,
  • Eman A. Ahmed,
  • Nathan Colasanti,
  • Robert H. Weber,
  • Alex Sparreboom,
  • Eric D. Eisenmann

摘要

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.