Predicting drug–drug interactions in breast cancer patients treated with CDK4/6 inhibitors and forward planning

ABSTRACT

Introduction

Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying drug–drug interactions (DDI) of these medications is of utmost importance.

Areas covered

This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. We discuss drug–drug interactions including those with proton pump inhibitors as well as CYP3A substrates, inhibitors, and inducers. We describe the effect of these drugs on membrane transporters and their substrates as well as those drugs that increase risk of CDK4/6 toxicities. Finally, we explore future directions for strategies to minimize drug–drug interactions.

Expert opinion

It is crucial to be mindful of medications that may interfere with drug absorption, such as proton pump inhibitors, as well as those that interfere with drug metabolism, such as CYP3A4 inhibitors and inducers. Additionally, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with greater comorbidities. These interactions and patient characteristics should be considered when developing individual treatment plans with CDK4/6 inhibitors.

KEYWORDS:

• Oncology
• breast
• CDK4/6 inhibitors
• drug–drug interactions
• pharmacokinetics
• palbociclib
• ribociclib
• abemaciclib

Article highlights

• CDK 4/6 inhibitors are a class of drugs currently approved for use in the treatment of HR+ breast cancer in the metastatic, and adjuvant setting. Due to their pharmacokinetics, they have many important drug–drug interactions.

• Absorption of CDK4/6 inhibitors is pH-dependent so concomitant use of PPIs should be avoided. If it cannot be avoided, ribociclib should be used preferentially as its absorption is less affected by pH than palbociclib.

• Due to their metabolism by the cytochrome P450 system in the liver, CDK4/6 inhibitors interact with inducers and inhibitors of CYP3A4. When taken with strong inhibitors and inducers of CYP3A4, dose adjustments may be recommended.

• CDK4/6 inhibitors are also inhibitors of many transporters and as such, lead to interactions with their substrates.

• CDK/6 inhibitors are associated with toxicities such as QTC prolongation and hepatotoxicity. Concomitant use of other medications with similar toxicity profiles should be avoided.

• Therapeutic drug monitoring and physiologically based pharmacokinetic models have been proposed as methods for mitigating against drug–drug interactions.

• Unique patient characteristics including their comorbidities and concomitant medication profile should be taken into account when prescribing CDK4/6 inhibitors.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.