Pharmacogenomic progress in individualized dosing of key drugs for cancer patients

Determining the correct dosage for the majority of chemotherapeutic agents presents a challenge for clinicians because there is a fine balance between doses that cause significant drug toxicity and loss of efficacy. This Review discusses the current limitations of body surface area-based dosing, provides examples of successful pharmacogenomics investigations that have used drug-metabolizing enzymes to decrease drug toxicity or improve efficacy, and highlights promising advances in pharmacogenomic-directed pharmacotherapy. 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/m 2 ; the FDA has recommended empirical dose reduction in patients who are homozygous for this allele Patients receiving tamoxi