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Determining the optimal dose in the development of anticancer agents

Nature Reviews Clinical Oncology volume 11, pages 272–281 (2014)Cite this article

Subjects

Key Points

  • The approved dose of anticancer drugs is often derived from empirical, small-scale studies rather than rationally conducted trials incorporating appropriate a priori assumptions

  • The pharmacokinetic profiles of an individual taking anticancer drugs are assumed to be associated with anti-tumour effects and toxicity patterns

  • Intra-individual variation in pharmacokinetics can be accounted for by patient-specific variables and environmental factors, but inter-individual variation in pharmacokinetics is also affected by pharmacogenetic factors

  • To personalize anticancer treatment, molecular characteristics of the tumour are important as well as information on environmental factors and germline genetic variability to achieve individualized drug dosing

Abstract

Identification of the optimal dose remains a key challenge in drug development. For cytotoxic drugs, the standard approach is based on identifying the maximum tolerated dose (MTD) in phase I trials and incorporating this to subsequent trials. However, this strategy does not take into account important aspects of clinical pharmacology. For targeted agents, the dose-effect relationships from preclinical studies are less obvious, and it is important to change the way these agents are developed to avoid recommending drug doses for different populations without evidence of differential antitumour effects in different diseases. The use of expanded cohorts in phase I trials to better define MTD and refine dose optimization should be further explored together with a focus on efficacy rather than toxicity-based predictions. Another key consideration in dose optimization is related to interindividual pharmacokinetic variability. High variability in intra-individual pharmacokinetics has been observed for many orally-administered drugs, especially those with low bioavailability, which might complicate identification of dose–effect relationships. End-organ dysfunction, interactions with other prescription drugs, herbal supplements, adherence, and food intake can influence pharmacokinetics. It is important these variables are identified during early clinical trials and considered in the development of further phase II and subsequent large-scale phase III studies.

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Figure 1: Schematic figure describing the therapeutic window (or range, or index).
Figure 2: Simplified summary of the evolution of GIST over time and its relationship to imatinib sensitivity.
Figure 3: Key factors influencing the systemic exposure to an anti-cancer drug.

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Acknowledgements

This work was supported in part by the American Lebanese Syrian Associated Charities (ALSAC) and National Institutes of Health grant NCI 5R01CA151633-04 (granted to A.S.)

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  1. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 CE, Netherlands

    Ron H. J. Mathijssen & Jaap Verweij

  2. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, 38105, TN, USA

    Alex Sparreboom

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Mathijssen, R., Sparreboom, A. & Verweij, J. Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 11, 272–281 (2014). https://doi.org/10.1038/nrclinonc.2014.40

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