Optimization of cyclosporine therapy.
Cyclosporine is a potent tool in the immunosuppressive armamentarium. It provides relatively selective inhibition of T-cell responses without dampening nonspecific resistance. However, its use is confounded by a pleiotropic array of side effects, the most important of which is renal dysfunction with the not uncommon sequelae of hypertension, hyperuricemia, and hyperkalemia. The hepatic injury associated with CyA administration, which is characterized by a chronic elevation of serum transaminase values, is potentiated by azathioprine or recrudescent or de novo viral infections. Finally, the proclivity of the drug to produce hyperlipidemia may jeopardize long-term survival; patients not infrequently require gemfibrizol and/or pravastatin therapy to control triglyceride and/or cholesterol levels, respectively. Two strategies appear to be useful. Our concentration-control strategy assesses CyA exposure by analyzing serial pharmacokinetic profiles, titering drug doses to achieve initial steady state concentrations of 400 ng/mL during continuous i.v. infusion, and to achieve average concentrations, namely AUC divided by dosing interval (in hours), of 550 ng/mL initially with trough levels of 200 ng/mL or above. Pretransplant pharmacokinetic profiling permits prediction of the appropriate initial i.v. dose in 73% of patients, and in combination with a posttransplant profile of the oral dose in about 60% of patients. The target oral concentrations are progressively reduced, thereby permitting prospective CyA control and minimizing adverse effects. The second synergistic drug strategy uses the median effect mathematical model to identify new drug combinations. The combination of CyA with RAPA, a macrolide which inhibits lymphokine signal transduction, and with BQR, a difluoro quinoline carboxylic acid analog that inhibits pyrimidine biosynthesis, permits at least a 20-fold reduction of the CyA dose in rat allograft models as well as prevents the activation of some CyA-resistant rejection pathways. Future investigations of pharmacologic strategies are undoubtedly likely to re-enforce the efficacy and safety of CyA administration for a range of immunologic disorders.
Kahan
B D
BD
Department of Surgery, University of Texas Medical School, Houston 77030.
D016572:Cyclosporine / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans
D016572:Cyclosporine