Potential drug–drug interactions with mitogen-activated protein kinase (MEK) inhibitors used to treat melanoma

ABSTRACT

Introduction

The management of patients with BRAF-mutated advanced melanoma who are undergoing targeted therapy with MEK inhibitors can be complicated by the co-administration of multiple medications, which can give rise to drug–drug interactions of clinical significance.

Covered areas

Our review presents a comprehensive analysis of the pharmacokinetic and pharmacodynamic interactions of the three approved for advanced melanoma MEK inhibitor drugs – binimetinib, cobimetinib, and trametinib. MEDLINE (PubMed) was utilized for the literature search, comprising clinical studies, observational studies, and preclinical research. The review discusses the impact of these interactions on efficacy and safety of the treatments and differentiates between interactions supported by pharmacokinetic or pharmacodynamic mechanisms, those encountered in clinical practice, and those observed in preclinical studies.

Expert opinion

Physicians should be aware about potential benefits, but also increased toxicity caused by drug interactions between MEK inhibitors and other drugs in the management of patients with metastatic melanoma.

KEYWORDS:

• MEK inhibitors
• BRAF inhibitors
• pharmacokinetics
• pharmacodynamics
• side-effects
• synergistic interactions

Article highlights

• Drug–drug interactions with mitogen-activated protein kinase inhibitors (MEKis) can significantly impact the management of patients receiving MEKis, given the complexity of managing the target therapy drug side effects.

• The simultaneous intake of other drugs can reduce or increase the concentration of MEKis in plasma, owing to pharmacokinetic drug–drug interactions, thereby altering their therapeutic efficacy.

• The vast majority of pharmacodynamic interactions studied with MEKis to date are synergistic in nature.

• Physicians should be aware about the potential benefits, but also the increased toxicity caused by drug interactions between MEKis and other drugs in the management of patients with metastatic melanoma.

Declarations 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.

Authors contributions

A Marani and H Gioacchini: conceptualization; visualization; writing – original draft. M Paolinelli: conceptualization. A Offidani: supervision. A Campanati: conceptualization; visualization, writing – review, supervision. All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This paper was not funded.