Therapeutic drug monitoring of oral targeted antineoplastic drugs

Abstract

Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.

Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

“…Nevertheless, Bayesian estimates also have their drawbacks. To use this method prior awareness of patients' characteristics, which are sometimes not available or hard to determine, is desirable, because otherwise the estimation will be guided towards the typical population mean [3,15]. Eventually this will lead to loss of individual information of the patient.…”

“…Eventually this will lead to loss of individual information of the patient. Moreover, a previously described PK model, specialized software and knowledge is needed to execute and interpret these calculations [3,36]. In contrast to Bayesian estimates, the method we used is simple to execute in clinical practice and does not depend on which model has been chosen.…”

“…SMKIs changed the treatment paradigm towards a targeted therapy approach with oral anticancer drugs instead of the traditional intravenous chemotherapy as cancer treatment. For many SMKIs an exposure-response relation has been published in recent literature [1][2][3]. Despite the narrow therapeutic window and large inter-patient variability, they are still prescribed at a fixed dose [4][5][6][7][8][9][10].…”

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

“…As it is common procedure to increase the dose in fixed increments, i.e., in 10 mg steps due to available tablet strengths, the dosing strategy (iv) aimed to represent the status-quo of dose adjustments to increase drug concentrations in clinical practice [ 33 , 37 , 38 , 44 ]. Representing the common clinical practice to measure minimum concentrations [ 45 ], we chose to collect our virtual TDM samples at the end of a dosing interval. However, as fluctuations in endoxifen concentrations within a steady-state dosing interval are minimal [ 46 ], our results are also applicable to different times of sample collection once a steady-state has been attained.…”

Clinical Importance of Plasma Drug Concentration of Oral Molecular Targeted Drugs for Renal Cell Carcinoma

“…Therapeutic drug monitoring (TDM) is widely used in clinical practice for maximizing the efficacy and minimizing the toxicities of certain drugs. Recently, TDM has also been recommended and applied to anticancer drug therapy (12)(13)(14). TDM of methotrexate for leukemia and fluorouracil for colorectal cancer were reported to improve the clinical outcomes of cancer chemotherapy (15,16).…”