Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Abstract

Although kinase inhibitors (KI) frequently portray large interpatient variability, a ‘one size fits all’ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels—i.e., therapeutic drug monitoring (TDM)—could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

“…Among 77 approved KIs, relationships between exposure-response and exposure-toxicity have been established in 26 drugs and 46 ones, respectively. 37 However, only three guidelines were developed for TDM of small molecule KIs.…”

Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study

“…Numerous tyrosine kinase inhibitors (TKIs) have been developed in recent years, and further studies are needed to optimize clinical recommendations, which often advocate single doses despite significant pharmacokinetic (PK) variability [ 7 , 18 ]. This study will focus on trametinib, which is widely used in clinical practice for the treatment of melanoma, for which a PK–efficacy relationship has been observed [ 18 ].…”

“…Numerous tyrosine kinase inhibitors (TKIs) have been developed in recent years, and further studies are needed to optimize clinical recommendations, which often advocate single doses despite significant pharmacokinetic (PK) variability [ 7 , 18 ]. This study will focus on trametinib, which is widely used in clinical practice for the treatment of melanoma, for which a PK–efficacy relationship has been observed [ 18 ]. Trametinib is a targeted therapy for the treatment of solid tumours in patients with the V600 mutation in the BRAF gene, which encodes a serine/threonine protein kinase that leads to the activation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) signalling pathway (see Figure 1 ) [ 19 ].…”

“…Meanwhile, these adverse effects increase the risk of treatment discontinuation. This poor adherence could have a considerable impact on the efficacy of trametinib, leading to a decrease in plasma concentrations, potentially bringing them below the efficacy threshold defined for this drug [ 18 ].…”

Population Pharmacokinetics in Oncology and Its Clinical Applications

“…We firmly advocate that both qualitative and quantitative aspects of cancer treatment must be considered as part of the precision oncology concept: it encompasses not only the selection of the best anti-cancer agents on the basis of tumor genetic biomarkers, but also the precise individualization of their dosage in each patient. Dosage individualization should be based on both the thorough adaptation to influential patient characteristics (a priori dosage adjustment) and the measurement of plasma circulating drug concentrations (a posteriori adjustment, i.e., therapeutic drug monitoring; TDM) [ 9 , 10 , 11 ]. These quantitative issues are the focus of pharmacometrics, a discipline that has undergone a remarkable evolution over the last few decades, but of which oncology and cancer patients have yet to take full advantage of.…”