EFFICACY AND PHARMACOKINETICS OF SIMVASTATIN IN HEART-TRANSPLANT RECIPIENTS

OBJECTIVE: To evaluate the efficacy and safety of simvastatin administ ered to a group of heart transplant patients receiving triple-drug imm unosuppressive therapy. We also assessed the potential pharmacokinetic interaction between simvastatin and cyclosporine by comparing mean pl asma concentrations of simvastatin beta-hydroxy acid, the major metabo lite of the drug, in a group of heart transplant patients treated with cyclosporine and in a control group of patients who had not received heart transplants. Both groups received long-term (>6 wk) simvastatin therapy. DESIGN: We monitored hyperlipidemia in 20 hypercholesterolemi c heart transplant patients receiving simvastatin 10 mg/d and triple-d rug immunosuppressive therapy. Changes in laboratory results before an d after 4 months of simvastatin therapy were considered. The same labo ratory data were monitored in a control group of 20 nonhypercholestero lemic heart transplant patients who were not treated with simvastatin but were receiving triple-drug immunosuppressive therapy. Plasma conce ntrations of simvastatin beta-hydroxy acid were measured in 14 hyperch olesterolemic patients, 7 of whom had received heart transplants and 7 who had not. SETTING: The Division of Cardiology and the First Medica l Clinic for the clinical study, as well as the Department of Pharmaco logy for the pharmacokinetic analysis. PARTICIPANTS: Forty heart trans plant patients and 7 hypercholesterolemic nontransplant patients. MAIN OUTCOME MEASURES: Effectiveness of simvastatin was determined by comp aring cholesterol and lipoprotein plasma concentrations in 20 patients who underwent heart transplant and were treated with simvastatin for 4 months. The safety of the drug was determined by analyzing changes i n laboratory results in the treated group and in the control group, bo th those who had received heart transplants and those who had received immunosuppressive therapy. RESULTS: After 4 months of simvastatin the rapy, total cholesterol decreased by 12.5% and low-density lipoprotein cholesterol decreased by 21.3%. The only statistically significant la boratory change was an increase of 28.7% in the alanine aminotransfera se concentrations. Plasma concentrations of simvastatin beta-hydroxy a cid were higher in heart transplant patients than in those who had not received heart transplants, the control group. CONCLUSIONS: Low-dosag e simvastatin treatment seems to be safe and sufficiently effective to decrease cholesterol concentrations. Concomitant treatment with immun osuppressive therapy (primarily cyclosporine) in heart transplant pati ents appeared to cause a reduced metabolic clearance of simvastatin fr om the plasma. More extensive studies on the interaction between simva statin and cyclosporine are needed to understand the marked variabilit y found in the response to simvastatin.