Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy

Although cyclosporine (CsA) displays high immunosuppressive efficacy due to potent selective inhibition of T cell, but not nonspecific, immune functions, the pleiotropic toxicities of the drug result in a low therapeutic index. Thus for a given individual there is at best only a narrow dosage range producing immunosuppression not beclouded by toxicity. Selection of the appropriate CsA dose to achieve this state is complicated by marked inter- and intraindividual variability in drug pharmacokinetics and pharmacodynamics (1). Even considering renal transplant recipients solely, pharmacokinetic variations in drug absorption, volume of distribution, and metabolism as estimated by clearance rates are so great that strategies based on median population values are not useful for a great proportion of patients. Thus it is necessary to devise a CsA strategy that tailors therapy to compensate for interindividual variations. Implementation of such a strategy not only standardizes drug therapy, but also reveals the clinical impact of interindividual differences in the profile of CsA metabolites and in pharmacodynamic effects of a given quantity of CsA, reflecting both the therapeutic actions on the immune system and toxic effects on target organs. Thus a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variation is essential for the eventual dissection of a rational CsA regimen.