Pharmacokinetics and Pharmacodynamics of Fluvastatin in Heart Transplant Recipients Taking Cyclosporine A

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Abstract
During the last decades, transplantation has become an established tool for the treatment of terminal organ failure. Beside immunological factors, hyperlipidemia is the main problem after heart transplantation, causing rapid transplant coronary artery disease (TxCAD) and poor long-term prognosis at the beginning of the transplantation. Heart transplant recipients are now effectively treated with lipid lowering substances, of which HMG-CoA-reductase inhibitors are the most potent. However, treatment with these substances correlates with an increased risk for the development of rhabdomyolysis due to therapy with the immunosuppressive cyclosporine A. Our study monitored the safety and efficacy of treatment with the HMG-CoA reductase inhibitor fluvastatin in heart transplant recipients compared to healthy controls. We investigated 10 patients receiving immunosuppressive therapy consisting of cyclosporine A, prednisone, and azathioprine who had increased concentrations of LDL-cholesterol (LDL-C), and 10 age-matched healthy controls. The patients were treated with 40 mg/day fluvastatin for 4 weeks and 20 mg/day for 4 additional weeks. Control individuals received 40 mg/day fluvastatin for 4 weeks only. Parameters of fluvastatin pharmacokinetics (maximum concentration of the drug (Cax,), time (tmax) to reach Cmax, area under the concentration vs. time curve (AUCOh 24h), elimination halflife time (t,2)), apparent total body clearance (CL), blood cyclosporine A concentration, plasma lipids, and safety parameters were determined in both study groups at the beginning of the study and after 4 weeks. The latter were determined in the patient group also after 8 and 12 weeks. Treatment with 40 mg/day fluvastatin caused a significant decrease in total cholesterol (patients: 5.47 ± 1.32 mmol/L vs. 7.30 ± 1.83 mmol/L; controls: 4.69 ± 0.64 mmolIL vs. 5.81 ± 0.72 mmol/L), LDL-C (patients: 3.28 + 1.25 mmol/L vs. 5.00 ± 1.85 mmol/L; controls: 2.58 ± 0.63 mmol/L vs. 3.50 ± 0.70 mmolJL), and triglycerides (patients: 1.99 ± 0.77 mmol/L vs. 2.50 ± 1.00 mmol/L; controls: 1.24 ± 0.46 mmolIL vs. 1.72 ± 0.67 mmol/L) in both study groups, whereas HDL-C was not significantly changed (patients: 1.29 ± 0.35 mmol/L vs. 1.17 ± 0.32 mmol/L; controls: 1.55 ± 0.30 mmol/L vs. 1.53 ± 0.26 mmol/L). Values of C,,m, and AUCOh 24h were higher in the patient group than in the control group (day 1, patients vs. controls, Cma,: 869.4 ± 604.0 ng/mL vs. 211.9 ± 113.9 ng/mL; AUCOh24h: 1948.8 ± 1347.9 ng/mL*h vs. 549.4 ± 247.4 ng/mLh), whereas the corresponding value of CL was lower in the patient group (33.3 ± 24.5 L/h vs. 107.9 ± 95.8 L/h), and the values of t,,,. and t,2showed no differences. In addition, values of C,,m, and AUCOb 24h after administration of 40 mg/day fluvastatin for 4 weeks in both groups were slightly higher than at the beginning, whereas the value of CL was slightly lower (day 28, patients vs. controls, C,,a,: 1530.4 ± 960.4 ng/mL vs. 254.7 ± 199.8 ng/mL; AUCOb-240: 2615.3 ± 1379.4 ng/mL*h vs. 841.8 ± 421.4 ng/mL*h; CL: day 28, 21.4 ± 15.3 L/h vs. 61.5 ± 36.6 L/h). Except for an intermittent increase of creatine kinase, safety parameters showed no increases within the observation period. Our data suggest that fluvastatin effectively lowers plasma concentrations of cholesterol and LDL-C in patients after heart transplantation, however, the metabolism of fluvastatin is affected by concomitant therapy with cyclosporine A. Serum concentrations of fluvastatin should be monitored in cases of concomitant therapy with other substances interfering in the metabolism by competing cytochrome enzymes.