CPD Bulletin CB V9 N1.indd

The measurement of plasma concentrations of drugs given in therapy (therapeutic drug monitoring, TDM) is useful for a small number of compounds for which pharmacological effects cannot be easily assessed and for which the margin between adequate dosage and potentially toxic dosage is small. Thus, for some anticonvulsants, notably phenytoin, anti-infective agents (antimalarial, antimicrobial, and antiretroviral drugs), cardioactive drugs including digoxin, most immunosuppressants, and certain psychoactive drugs (notably clozapine and lithium), TDM may be used to adjust the dose to individual need and to minimize the risk of dose-related toxicity. Even for drugs with a wide margin of safety, TDM may be helpful in assessing adherence to therapy as a reason for treatment failure. An appreciation of drug metabolism and of pharmacokinetics, the study of the rates of drug absorption, distribution, metabolism and elimination, is essential in understanding the influence of age, sex, other genetic variables, disease, and other parameters on the time course and clinical effect of drugs in the body. The availability of a range of non-isotopic immunoassays compatible with high-throughput clinical chemistry analyzers has meant that certain TDM assays are widely available, but in many cases chromatographic methods (nowadays usually HPLC or LC-MS) have to be used. Whatever technique is used when providing a TDM service, adherence to the principles of quality management (proper method implementation and validation, and adherence to internal quality control and external quality assessment procedures) is essential since treatment decisions may be based on the results. Keyword Pharmacokinetics, lithium, digoxin, psychoactive drugs. Introduction The measurement of plasma concentrations of drugs given in therapy is useful for a small number of compounds for which pharmacological effects cannot be assessed easily and for which the margin between adequate dosage and potentially toxic dosage is small. However, assays for a much wider range of compounds, and sometimes metabolites, may be requested to assess adherence (compliance, concordance) to therapy or to investigate and if possible prevent adverse treatment effects, drugdrug interactions, or acute poisoning (Box 1). For some agents drug dosage can be monitored indirectly (Box 2). However, drug assays may still be requested, for example in patients in whom antihypertensive therapy appears refractory to treatment and adherence is questioned. In all TDM work it is important to bear in mind the purpose for which the analysis has been undertaken when reporting and interpreting analytical results. With some analytes such as metals/trace elements there is a true ‘normal’ or ‘normally-expected’ range to provide a basis for interpreting results. This is the case with lithium because small amounts of lithium are present in the diet. However, when lithium carbonate is used as a drug to treat bipolar disorder (mania), for example, research has shown that there is a range of plasma lithium ion concentrations (0.6–1.0 mmol L) that is associated with optimal therapeutic benefit and minimal risk of toxicity. Such a range may be referred to as the ‘therapeutic range’, ‘reference range’, ‘target range’, or ‘therapeutic window’. Lithium is a toxic drug. Mild adverse effects can occur even at plasma concentrations of 1 mmol L when lithium is given chronically, with mild to moderate toxicity being expected at 1.5–2 mmol L, although patients in a manic state do seem to have an increased tolerance to the drug. Severe toxicity is likely above 2 mmol L. Initial features of toxicity may include gastrointestinal discomfort, Therapeutic Drug Monitoring (TDM) Robert J Flanagan Toxicology Unit, Department of Clinical Biochemistry, Bessemer Wing, King’s College Hospital NHS Foundation Trust Denmark Hill, LONDON, SE5 9RS Nigel W Brown Immunosuppressant Drug Monitoring Service Institute of Liver Studies, King’s College Hospital NHS Foundation Trust Denmark Hill, LONDON, SE5 9RS Robin Whelpton School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, LONDON, E1 4NS