Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

Abstract

Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations

“…Age-related inter-individual variability has already been demonstrated for many treatments, but not for all TKIs [ 47 , 48 ]. Data are only available for vemurafenib [ 5 , 49 ].…”

Phenotype versus genotype to optimize cancer dosing in the clinical setting—focus on 5‐fluorouracil and tyrosine kinase inhibitors

“…40 Yet, retrospective audits of TKIs in clinical practice have shown that achievement of targeted drug exposure correlates with treatment response with, for example, imatinib, nilotinib, dasatinib, erlotinib, sunitinib, and sorafenib. 41,42 The following table…”

“…Furthermore, genetic testing cannot measure patient characteristics such as adherence to treatment, a known impact on clinical outcome, nor environmental factors (food–drug and drug–drug interactions, including pharmacodynamic and other non‐P450 drug interactions) 40 . Yet, retrospective audits of TKIs in clinical practice have shown that achievement of targeted drug exposure correlates with treatment response with, for example, imatinib, nilotinib, dasatinib, erlotinib, sunitinib, and sorafenib 41,42 . The following table summarizes such points (Table 3).…”

Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review

“…Furthermore, TDM was typically considered advantageous for drugs with a large inter-individual variability in exposure with relatively low intra-individual variation, a significant exposure–efficacy relationship, a narrow therapeutic window, and the availability of a validated bioanalytical assay. It has been postulated recently that this could also represent a useful tool to individualize dosing and optimize treatment using drugs with a wide therapeutic window and high cost [ 22 ].…”