Individualizing BU Treatment-Path From PK-Guided Dosing to Genetic Marker-Guided Dosing
It is well established that dose targeting based on therapeutic drug monitoring seems to improve treatment-related mortality, event-free survival and overall survival rates, compared with BU treatment without therapeutic drug monitoring.[1,17] Despite these improvements, inter-patient variability still exists and the percentage of pediatric patients reaching the target area under the concentration time curve (AUC) after the first dose remains low.[1,18] Several factors have been identified to account for differences such as weight, body surface area, age and sex.[14,19] In adults, an AUC of 900–1500 μM.min (equivalent to a Css between 616 and 1026 ng/ml) after first dose is a suitable therapeutic range when BU is administered in a conventional schedule. Nevertheless, optimal target AUC/Css of intravenous BU in children undergoing HSCT remains unclear. It is also important to note the fact that first dose PK of BU is associated with clinical outcomes, and treatment related mortality.[7,10] Of note, in our cohort we observed an increased dose requirement in GSTA1*A2 carriers for achieving the target range Css, although most of the patients with adjusted doses did not have plasma levels above the therapeutic range but still there was a difference of Css in carriers versus noncarriers of GSTA1*A2 after dose adjustment. The dose requirement followed similar pattern in relation to GSTM1 genotypes in patients older than 4 years with less doses in null carriers corresponding to the lowered BU CL in these individuals. These observations highlight the importance of initial exposures of patients to BU and to recommend personalized initial doses. This could be achieved, for example, by estimating dose based on demographics and genetic factors combined to achieve better outcomes of treatment as being practiced for some other drugs across all specializations of medicine such as warfarin, abacavir, clopidogrel, 6-mercaptopurine and azathioprine. Dosing schedules based on genetic polymorphisms in metabolizing enzymes or targets for these agents allows personalizing treatment protocols.
Pharmacogenetic testing of GST genes may not only be important for individualizing BU dosing but this approach may also be beneficial for individualizing the treatment protocols for other electrophilic chemotherapeutic agents (e.g., nitrogen mustards, environmental toxins) predominantly eliminated by GSH conjugation. Furthermore, GST genetic testing might also serve as an indicator of cellular integrity in response to oxidative stress and dynamics of endogenous electrophilic compounds.
Personalized Medicine. 2014;11(5):463-466. © 2014 Future Medicine Ltd.