Pharmacogenomic Progress in Individualized Dosing of Key Drugs for Cancer Patients

Christine M. Walko; Howard McLeod

Nat Clin Pract Oncol. 2009;6(3):153-162.

Summary and Review Criteria

Summary

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.

Review Criteria

Articles were identified by searching the PubMed database for relevant publications written in English from 1966 until 1 September 2008. Abstracts from ASCO published until June 2008 were also reviewed. The search terms included "anticancer drugs", "pharmacogenomics", "pharmacokinetics", and "pharmacodynamics". Studies from the identified literature were chosen based on the best clinical evidence that addressed this article's objectives. Results of data analysis performed by the authors are also included.

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Cite this: Pharmacogenomic Progress in Individualized Dosing of Key Drugs for Cancer Patients - Medscape - Mar 01, 2009.

Box 1. Sources of Variation in Drug Disposition and Effect
Human factors
Patient adherence to treatment Clinician adherence Medication access
Pharmacokinetic factors
Drug interactions Induction and/or inhibition of cytochrome P450 enzymes Genetic variation in metabolism or transport genes
Pharmacodynamic factors
Genetic variation in drug targets Drug interactions Diet (e.g. need for folic acid with methotrexate therapy)

The Effect of Polymorphisms in Glucuronidation Enzymes^a on Risk of Irinotecan Toxicity
Reference	Irinotecan dosage	Study design	Sample size (n)	Pharmacokinetic relationship	Toxicity relationship
Ando et al. (2000)^[27]	Various doses and schedules	Retrospective	118	NE	7/7 Genotype had 5.2-fold risk of grade 4 leukopenia and/or grade 3 or 4 diarrhea (P <0.001)
Iyer et al. (2002)^[26]	300 mg/m² over 90 min	Prospective	20	7/7 Genotype SN-38 glucuronidation ratio is 3.9-fold lower than in 6/6 genotype (P = 0.001)	7/7 Genotype had 2.5-fold lower ANC nadir than 6/6 genotype (P = 0.04)
Marcuello et al. (2004)^[57]	Various doses and schedules	Retrospective	95	NE	7/7 Genotype had a 4.1-fold increased occurrence of grade 3 or 4 diarrhea compared with 6/6 genotype (P = 0.005)
Innocenti, et al. (2004)^[25]	350 mg/m² over 90 min	Prospective	66	7/7 Genotype SN-38 glucuronidation ratio is 1.8-fold lower than in 6/6 genotype (P = 0.03)	7/7 Genotype had 9.3-fold risk of grade 4 leukopenia (P = 0.001)
Rouits et al. (2004)^[58]	85 or 180 mg/m² over 90 min + fluorouracil + leucovorin (FOLFIRI)	Retrospective	75	NE	7/7 Genotype had a 7.4-fold increased occurrence of grade 3 or 4 hematologic toxicity compared with 6/6 genotype (P = 0.001)
Toffoli et al. (2006)^[59]	180 mg/m² over 120 min + fluorouracil + leucovorin (FOLFIRI or modified FOLFIRI)	Prospective	250 (PK in 71)	7/7 Genotype SN-38 glucuronidation ratio is 2.0-fold lower than in 6/6 patients (P = 0.01)	7/7 Genotype had 8.6-fold risk of grade 3 or 4 hematologic toxicity compared to 6/6 genotype (P = 0.02)
Pillot et al. (2006)^[60]	200 mg/m² over 90 min + carboplatin AUC 5	Prospective	42	NE	7/7 Genotype had a 2.8-fold increased occurrence of grade 4 neutropenia compared with 6/6 genotype (P = 0.09)

^aUGT1A1^*28 is the most common variant of the UGT1A1 gene, with seven TA repeats in the promoter region. Carriers of this variant have enzymes with a lower glucuronidating activity than those who have wild-type UGT1A1^*1 alleles that have six TA repeats in their promoter region. Abbreviations: 6/6 = UGT1A1^*28 wild-type alleles; 7/7 = UGT1A1^*28 homozygous variant alleles that confer a reduced-glucuronidation phenotype; ANC = absolute neutrophil count; AUC = area under the curve; FOLFIRI = a chemotherapy regimen consisting of irinotecan plus 5-fluorouracil and leucovorin; NE not evaluated; PK = pharmacokinetic; UGT1A1^*28 and the 6/6 = 7/7 genotypes.

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