Evaluating the utility of therapeutic drug monitoring in the clinical use of small molecule kinase inhibitors: a review of the literature

ABSTRACT

Introduction: Orally administered small molecule kinase inhibitors (KI) are a key class of targeted anti-cancer medicines that have contributed substantially to improved survival outcomes in patients with advanced disease. Since the introduction of KIs in 2001, there has been a building body of evidence that the benefit derived from these drugs may be further enhanced by individualizing dosing on the basis of concentration.

Areas covered: This review considers the rationale for individualized KI dosing and the requirements for robust therapeutic drug monitoring (TDM). Current evidence supporting TDM-guided KI dosing is presented and critically evaluated, and finally potential approaches to address translational challenges for TDM-guided KI dosing and alternate approaches to support individualization of KI dosing are discussed.

Expert opinion: Intuitively, the individualization of KI dosing through an approach such as TDM-guided dosing has great potential to enhance the effectiveness and tolerability of these drugs. However, based on current literature evidence it is unrealistic to propose that TDM-guided KI dosing should be routinely implemented into clinical practice.

KEYWORDS:

• Concentration-guided dosing
• kinase inhibitors
• precision medicine
• therapeutic drug monitoring

Article highlights

• Multiple kinase inhibitors exhibit exposure-effect relationships for both efficacy and toxicity at doses achieved with standard dosing.

• Between subject variability in kinase inhibitor exposure ranges from low (dasatinib) to high (axitinib) and for many KIs results in a substantial proportion of patients achieving an exposure below proposed target concentration.

• The two major limitations to the routine implementation of TDM-guided KI dosing are (1) the lack of independent, prospectively reproduced target concentrations, and (2) the lack of evidence demonstrating superior treatment benefit in patients dosed based on a TDM-guided dosing protocol compared to a flat dosing protocol.

• Based on current literature there is insufficient evidence to support the routine implementation of TDM-guided KI dosing into clinical practice.

Declaration of interest

A Rowland and M J Sorich are recipients of unrelated research support from Pfizer Inc. The authors have no other 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.