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Pharmacogenomic progress in individualized dosing of key drugs for cancer patients

Nature Reviews Clinical Oncology volume 6, pages 153–162 (2009)Cite this article

Abstract

Determining the correct dosage for the majority of traditional chemotherapeutic agents presents a challenge because most drugs have a narrow therapeutic index, which results in a fine balance between doses that cause significant drug toxicity and loss of efficacy. Dosing calculations for most agents use the patient's body surface area, a method that correlates poorly with drug pharmacokinetics. Genetic differences in drug-metabolizing enzymes are being evaluated in an effort to explain the pharmacokinetic and pharmacodynamic variability seen with many chemotherapeutic agents. Elucidation of the underlying reasons for this variability will enable individualization of therapy to minimize toxicity and maximize efficacy, and thus improve control over the narrow therapeutic index of these agents. Such investigations have led to Clinical Pharmacology FDA Subcommittee recommendations for changes to drug package instructions. This Review discusses the current limitations of body-surface-area-based dosing, examples of successful pharmacogenomic investigations that have used drug-metabolizing enzymes to decrease drug toxicity and/or improve efficacy, and the future promises of pharmacogenomic-directed pharmacotherapy.

Key Points

  • The majority of chemotherapeutic agents are dosed according to the patient's body surface area, which correlates poorly with drug pharmacokinetics

  • Genetic differences in drug-metabolizing enzymes partially explain the interindividual pharmacokinetic variability of many anticancer agents

  • Patients with thiopurine S-methyltransferase deficiency require 5–10% of the standard dose of thiopurine immunosuppressive agents to avoid severe hematologic toxicity

  • The UGT1A1*28 allele is associated with increased neutropenia and diarrhea in patients receiving irinotecan, especially at doses greater than 200 mg/m2; the FDA has recommended empirical dose reduction in patients who are homozygous for this allele

  • Patients receiving tamoxifen who are classified as CYP2D6 poor metabolizers, on the basis of either genotype or concurrent drug therapy, are likely to have a shorter time to relapse and lower disease-free survival than extensive metabolizers or patients who are homozygous for the wild-type CYP2D6 allele

  • An algorithm that uses patient's height, age and both VKORC1 and CYP2C9 genotypes has demonstrated the ability to account for 54.2% of the variability in warfarin dose requirements and could potentially improve the quality of care provided for patients receiving this anticoagulant

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Figure 1: Metabolism of irinotecan.
Figure 2: Metabolism of tamoxifen.
Figure 3: Comparison of outcomes between CYP2D6*4/*4 genotypes at 12 years post-randomization in patients receiving tamoxifen.
Figure 4: Metabolism of warfarin and vitamin K inhibition.

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Author information

Authors and Affiliations

  1. CM Walko is Assistant Professor in the Division of Pharmacotherapy and Experimental Therapeutics, North Carolina School of Pharmacy, and a clinical pharmacist and pharmacokineticist for the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.,

    Christine M Walko

  2. H McLeod is Fred N Eshelman Distinguished Professor and Director, of the University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.,

    Howard McLeod

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  1. Christine M Walko
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Correspondence to Howard McLeod.

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Competing interests

Dr Howard McLeod declared he is a consultant for Affymetrix and Myriad Genetics. CM Walko declared no competing interests.

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Walko, C., McLeod, H. Pharmacogenomic progress in individualized dosing of key drugs for cancer patients. Nat Rev Clin Oncol 6, 153–162 (2009). https://doi.org/10.1038/ncponc1303

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