Pharmacogenomic progress in individualized dosing of key drugs for cancer patients.
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.
Walko
Christine M
CM
Division of Pharmacotherapy and Experimental Therapeutics, North Carolina School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
McLeod
Howard
H
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor