Interactions of janus kinase inhibitors with drug transporters and consequences for pharmacokinetics and toxicity

ABSTRACT

Introduction: Janus kinase inhibitors (JAKinibs) constitute an emerging and promising pharmacological class of anti-inflammatory or anti-cancer drugs, used notably for the treatment of rheumatoid arthritis and some myeloproliferative neoplasms.

Areas covered: This review provides an overview of the interactions between marketed JAKinibs and major uptake and efflux drug transporters. Consequences regarding pharmacokinetics, drug-drug interactions and toxicity are summarized.

Expert opinion: JAKinibs interact in vitro with transporters in various ways, as inhibitors or as substrates of transporters or as regulators of transporter expression. This may theoretically result in drug-drug interactions (DDIs), with JAKinibs acting as perpetrators or as victims, or in toxicity, via impairment of thiamine transport. Clinical significance in terms of DDIs for JAKinib-transporter interactions remains however poorly documented. In this context, the in vivo unbound concentration of JAKinibs is likely a key parameter to consider for evaluating the clinical relevance of JAKinibs-mediated transporter inhibition. Additionally, the interplay with drug metabolism as well as possible interactions with transporters of emerging importance and time-dependent inhibition have to be taken into account. The role drug transporters may play in controlling cellular JAKinib concentrations and efficacy in target cells is also an issue of interest.

KEYWORDS:

• JAK inhibitor
• drug-drug interactions
• thiamine
• inflammation
• drug transporters
• pharmacokinetics

Article highlights

• Janus kinase inhibitors (JAKinibs) constitute an emerging class of anti-inflammatory or anti-cancer drugs.

• Marketed JAKinibs in vitro interact with the main drug transporters implicated in pharmacokinetics in various ways, i.e., acting as inhibitors, as substrates or as regulators of drug transporter expression; consequently, they may theoretically trigger drug-drug interactions as perpetrators or victims.

• The clinical significance of transporters-related drug-drug interactions due to JAKinibs remains currently poorly documented.

• The in vivo free concentration of JAKinibs, that is the effective one, is likely a key-parameter to consider for judging the clinical relevance of JAKinib-transporter interactions.. The JAKinib fedratinib inhibits the transport of the vitamin thiamine, which may cause neurologic toxicity.

• The uptake or efflux of JAKinibs mediated by transporters in target cells has to be considered as a possible important contributing factor to their intracellular accumulation and pharmacological efficacy.

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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.

Supplementary material

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