Ann Transplant 2009; 14(1): 11-11
More than 400 years ago, Paracelsus wrote, "A drug can be an inert substance, a poison, or a therapeutic agent dependent upon how it is used and the dosage in which it is given." This maxim is particularly appropriate to the use of immunosuppressive drugs, whose benefits can readily be offset by the potential toxic side effects when drugs are prescribed without due regard for the appropriateness of a specific drug for a specific patient. This mandates careful appraisal of the pharmacodynamic and pharmacokinetic properties of immunosuppressive drugs especially in centers where substitution between brand names and generics is often. Of major concern is the understanding that the pharmacokinetics of a drug can vary as a function of the formulation. Problems are particularly apt to arise when a pharmacist substitutes a generic drug for a brand-name drug, because the immunosuppressive properties or potential toxic effects of the two drugs may not be clinically equivalent. According to the American food and drug administration (FDA), only generics with ABA rating are switchable with each other or with the brand name without additional laboratory testing. In order for a drug to obtain ABA rating it has to be proven switchable in accordance to rule number FDA 505 J which states that if a drug product contains a drug substance that is chemically identical and is delivered to the site of action at the same rate and extent as another drug product, then it is equivalent and can be substituted (switched) for that drug product. The methods for establishing bioequivalence are defi ned in FDA Code of Federal Regulations (CFR) rule 21320, 24, and include the following steps: (1) pharmacokinetic studies; (2) comparative clinical trials; and (3) pharmacodynamic (Bioactivity) studies. Basically the pharmacokinetic is a single dose study with therapeutic drug monitoring at various points within a 24-48 hour period. Although this technique is quite valuable to compare different formulations of the same drug however, it is not sufficient by itself to gain the ABA rating. Long term clinical evaluation or alternatively pharmacodynamic studies are also required. To assess the bioactivity of any drug, the site of action must be. Known and the investigator must be able to make accurate, specific, and reproducible measurements of drug concentration at the site of action, and also identify and measure the response. Since the immunosuppressive effect of all these drugs are initiated by its binding to receptors on the lymphocytes surface, which leads to inhibition of the production of cytokines and the proliferation of activated lymphocytes. The effect of the bound drug on the lymphocyte is expressed as the decrease in the number of lymphocyte from an established base line (pre dose). Thus; it's more advantageous to monitor the level and the effect of these drugs at the site of their action (bioequivalence), the lymphocytes. In most clinical settings the therapeutic drug monitoring for both brand name and generic immunosuppressive drugs is perfumed using commercially available kits. These kits are helpful for guidelines however; they are neither specific nor accurate. Thus it is recommended that reference laboratories with HPLC and mass spectrophotometers are used for the evaluation of both the bioavailability and bioequivalence of generic immunosuppressive agents.
Keywords: HPLC, Transplantation