Precision Dosing of Targeted Therapies Is Ready for Prime Time

Abstract

Fixed dosing of oral targeted therapies is inadequate in the era of precision medicine. Personalized dosing, based on pharmacokinetic (PK) exposure, known as therapeutic drug monitoring (TDM), is rational and supported by increasing evidence. The purpose of this perspective is to discuss whether randomized studies are needed to confirm the clinical value of precision dosing in oncology. PK-based dose adjustments are routinely made for many drugs and are recommended by health authorities, for example, for patients with renal impairment or for drug–drug interaction management strategies. Personalized dosing simply extrapolates this paradigm from selected patient populations to each individual patient with suboptimal exposure, irrespective of the underlying cause. If it has been demonstrated that exposure is related to a relevant clinical outcome, such as efficacy or toxicity, and that exposure can be optimized by PK-guided dosing, it could be logically assumed that PK-guided dosing would result in better treatment outcomes without the need for randomized confirmatory trials. We propose a path forward to demonstrate the clinical relevance of individualized dosing of molecularly-targeted anticancer drugs.

An Easily Expandable Multi-Drug LC-MS Assay for the Simultaneous Quantification of 57 Oral Antitumor Drugs in Human Plasma

“…The high interindividual variability in plasma concentrations found in the present work and in previous publications [ 5 , 9 , 10 , 14 ] is likely due to multiple factors, such as varying time between intake of medication and blood sampling, variable patient adherence [ 6 , 16 ], and interactions with food and/or concomitant medications (e.g., acid reducing agents) [ 6 , 17 , 18 , 19 ]. Recently, we reported higher patient satisfaction, reduced side effects and medication errors under treatment with many new oral antitumor drugs when an intensified clinical pharmacological/pharmaceutical care program is applied on top of routine clinical care [ 8 ].…”

“…Most of the oral anticancer drugs—especially protein kinase inhibitors—are prescribed in a one dose fits all approach [ 6 , 9 , 10 ]. However, several clinical studies demonstrated considerable interindividual differences in drug exposure despite identical dosing [ 5 , 9 , 10 , 11 , 12 , 13 , 14 ], which can be considered as suboptimal. Imatinib, for example, showed varying plasma concentrations by a factor of 60 [ 15 ].…”

“…An analysis published by Groenland et al demonstrated that 38% of patients treated with 23 different oral anticancer drugs had plasma concentrations below the recommended range [ 14 ]. Previous publications made TDM-recommendations for multiple oral anticancer drugs [ 5 , 9 , 10 ]. Currently, there is a lack of appropriate methods to determine plasma concentrations for the wide variety of clinically used oral anticancer drugs.…”

Systematic Review With Meta-Analysis: Diagnostic, Prognostic and Clinicopathological Significance of CircRNA Expression in Renal Cancer

“…Nevertheless, more than 30% of patients will likely become resistant to targeted drugs. Therefore, it is particularly important to comprehensively study the mechanism of the occurrence and development of RC as well as the molecules involved to generate precise treatment plans for different patients (45).…”

Challenges of Systemic Therapy Investigations for Bone Sarcomas

“…For pediatric patients, another factor that makes the rapid evaluation of clinical trials difficult is the fact that dose-finding phase I studies must be conducted again from the beginning for new pediatric antitumor drugs, even for drugs that have been approved for efficacy and safety in adults. In recent years, a review of the dosing steps for pediatric patients and the individualization of drug dosages regardless of whether a pediatric population is involved have been studied, and it is expected that the results of efficacy evaluations will be obtained more quickly in the future [ 121 , 122 , 123 ].…”