Tacrolimus properties and formulations: Potential impact of product quality on safety and efficacy
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Tacrolimus (FK506), a macrolide antibiotic, is frequently used in solid organ transplantation. It is a strong immunosuppressive agent that produces its pharmacological effect through the inhibition of calcineurin, an intracellular protein required for the production of interleukin by T-cells and consequently, inhibits proliferation and maturation of T-lymphocytes. It is approved by the FDA to prevent allograft rejection including liver, kidney or heart as a monotherapy or in combination with azathioprine or mycophenolate mofetil. It also belongs to narrow therapeutic index drug class which often requires close therapeutic drug monitoring in order to prevent drug toxicity or therapeutic failure. Blood level of tacrolimus are routinely monitored in clinical practice to maintain within therapeutic range. It may produce neurotoxicity, nephrotoxicity, gastrointestinal toxicity, hyperkalemia, hypertension, and myocardial hypertrophy if its blood concentration shoots up to toxicological level. On the other hand, its subtherapeutic level in blood may stimulate the body to reject allograft. Additionally, tacrolimus is metabolized by both liver and intestinal cytochrome P450 (CYP3A4) and p-glycoprotein (P-gp) which represent huge potential for drug-drug interactions resulting in toxic or subtherapeutic blood level of tacrolimus. Many classes of drug are metabolized by CYP3A4 and P-gp which may often compete for metabolization pathway when administered together. In order to ensure optimum tacrolimus therapy in the presence of other medications, it first involves knowledge of potential several interactions, dose adjustment when required, and therapeutic or clinical monitoring at an appropriate timeduring the therapy to assess these interactions. An important factor for consistent therapeutic action is the drug product quality itself. Product variability might arise because of differences in manufacture, excipients used, stability profiles and bioinequivalence between products when they are switched from one manufacturer to another. This article reviews the important properties that determine the selection of a formulation approach and the potential impact of product quality performance on the safety and efficacy of its therapy 2013 Nova Science Publishers, Inc.
