FINDING IMATINIB OPTIMAL DOSAGE

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example.

Li-Wan-Po A, Farndon P, Craddock C, Griffiths M.

National Genetics Education and Development Centre, Morris House, c/o Birmingham Women's Hospital, Edgbaston, Birmingham, B15 2TG, UK, a.liwanpo@talk21.com.

PURPOSE: To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia METHODS: A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis. RESULTS AND DISCUSSION: One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 microM) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 microM. This is consistent with the results of other observational studies where dose-response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose-blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose-blood level and dose-clinical response relationships. CONCLUSION: A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 microM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.