Pharmacogenetics: the therapeutic drug monitoring of the future?

Abstract

Genetic variability in drug response occurs as a result of molecular alterations at the level of drug-metabolising enzymes, drug targets/receptors, and drug transport proteins. In this paper, we discuss the possibility that therapeutic drug monitoring (TDM) in the future will involve not the mere measurement and interpretation of drug concentrations but will include both traditional TDM and pharmacogenetics-oriented TDM. In contrast to traditional TDM, which cannot be performed until after a drug is administered to the patient. pharmacogenetics-oriented TDM can be conducted even before treatment begins. Other advantages of genotyping over traditional TDM include, but are not limited to, the following: (i) it does not require the assumption of steady-state conditions (or patient compliance) for the interpretation of results; (ii) it can often be performed less invasively (with saliva, hair root or buccal swab samples); (iii) it can provide predictive value for multiple drugs [e.g. a number of cytochrome P450 (CYP) 2D6, CYP2C 19 or CYP2C9 substrates] rather than a single drug; (iv) it provides mechanistic, instead of merely descriptive, information; and (v) it is constant over an individual's lifetime (and not influenced by concurrent drug administration, alteration in hormonal levels or disease states). Pharmacogenetic information can be applied a priori for initial dose stratification and identification of cases where certain drugs are simply not effective. However, traditional TDM will still be required for all of the reasons that we use it now. In current clinical practice, pharmacogenetic testing is performed for only a few drugs (e.g. mercaptopurine, thioguanine, azathioprine, trastuzumab and tacrine) and in a limited number of teaching hospitals and specialist academic centres. We propose that other drugs (e.g. warfarin, phenytoin, codeine, oral hypoglycaemics, tricyclic antidepressants, aminoglycosides, digoxin, cyclosporin, cyclophosphamide, ifosfamide, theophylline and clozapine) are potential candidates for pharmacogenetics-oriented TDM. However, prospective studies of phaymacogenetics-oriented TDM must be performed to determine its efficacy and cost effectiveness in optimising therapeutic effects while minimising toxicity. In the future, in addition to targeting a patient's drug concentrations within a therapeutic range, pharmacists are likely to be making dosage recommendations for individual drugs on the basis of the individual patient's genotype. As we enter the era of personalised drug therapy, we will be able to identify not only the best drug to be administered to a particular patient, but also the most effective and safest dosage from the outset of therapy.