Pharmacodynamic monitoring and pharmacogenetics
We began this section by defining TDM as the use of drug or metabolite measurements in body fluids as an aid to monitoring therapy. In recent years, other methods of controlling drug therapy have been introduced and, though they do not fit the strict definition of TDM, they merit brief mention as they are becoming increasingly important. Pharmacodynamic monitoring is the study of the biological effect of a drug at its target site, and has been applied in the areas of immunosuppressive therapy and cancer chemotherapy. For example, the biological effect of the immunosuppressant ciclosporin can be assessed by measuring the extent of inhibition of calcineurin phosphatase, or the interleukin-2 concentration of peripheral blood lymphocytes. The advantages of such monitoring are that it gives an integrated measure of all biologically active species (parent drug and metabolites), so therapeutic ranges can be defined more closely, and that it is free from the matrix and drug disposition problems that bedevil TDM for immunosuppressants. The main disadvantage of pharmacodynamic monitoring is that the assays involved are often significantly more complex and time-consuming than the measurement of a single molecular species by chromatography and immunoassay. It is too early to say whether pharmacodynamic monitoring will have a significant role to play in optimising therapy, but it is likely to prove an effective complement to TDM and pharmacogenetic studies.
Pharmacogenetic studies (studies of hereditary influences, including race, on pharmacological responses) have clear and wide-ranging clinical relevance. The enzymes that are responsible for metabolism of drugs and other compounds exhibit wide inter-individual variation in their protein expression or catalytic activity, and result in different drug metabolism phenotypes between individuals. This variation may arise from transient effects on the enzyme, such as inhibition or induction by other drugs, or may be at the gene level and result from specific mutations or deletions. Pharmacogenetic polymorphism is defined as the existence in a population of two or more alleles (at the same locus) that result in more than one phenotype with respect to the effect of a drug. The term ‘pharmaco genomics’ has recently been coined to describe the practice of designing drugs according to in dividual genotypes to enhance safety and/or efficacy, and undoubtedly represents a massive growth area for 21st-century medicine. Determination of an individual’s ability to metabolise a specific drug, either by administering a test dose of the drug or a compound metabolised by the same enzyme system (phenotyping) or by specific genetic analysis (genotyping) can inform and improve the clinician’s ability to tailor drug dosage to the specific requirements of the individual patient. For example, a number of enzymes of the cytochrome P450 superfamily show genetic polymorphisms that account for differences in clinical response. The CYP2D6 isoform metabolises a range of drugs widely used in medicine, including many anti-arrhythmics and antidepressants. Debrisoquine is also a substrate for this isoform, and debrisoquine hydroxylase activity determined by the rate of metabolism of a test dose of debrisoquine has been widely used to determine the CYP2D6 phenotype and the differentiation of poor metaboliser (PM), extensive metaboliser (EM) and ultra-extensive (=ultra-rapid) metaboliser (UEM) phenotypes. However, debrisoquine is no longer available, and dextromethorphan has replaced it as a probe drug for clinical use. Alternatively, genetic analysis can be used to define the CYP2D6 phenotype and identify the alleles associated with the PM phenotype (of which the most common are CYP2D6 *3, *4, *5, *6 and *7). Once determined, the phenotype or genotype can be used to guide the dosage for any of the drugs metabolised by the CYP2D6 isoform. The CYP2D6 enzyme is absent in 5–10% of caucasians, CYP2C19 is absent in 15–30% of Asian people. Some drugs are inhibitors and other enzyme inductors on CYP enzyme 3A4, 2D6, 2C19, 2C9 and/or 1A2. The combination of classical TDM, pharmaco dynamic biomarkers and pharmacogenetics will undoubtedly accelerate the development and facilitate the clinical use of drugs, and will have a major role in delivering therapeutic efficiency and improved patient outcome with less need for plasma concentration monitoring.
