Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A

Background: Heart transplantation is an established tool for the treatment of terminal heart failure. Hyperlipidemia is a common problem following heart transplantation and has been implicated as an additional risk factor in the development of transplant coronary artery disease (TxCAD). Therefore, heart recipients are commonly treated with inhibitors of cholesterol synthesis (HMG-CoA reductase inhibitors). However, these patients have an increased risk of developing rhabdomyolysis due to elevated concentrations of HMG-CoA reductase inhibitors under co-administration with the immunosuppressive cyclosporin A (CsA). Aim of the study: Aim of our study was to obtain pharmacokinetic data on pravastatin whilst monitoring the safety and efficiency of the lipid lowering therapy in heart-transplant recipients under immunosuppression with CsA and to compare these data to those of a healthy control group. Subjects, materials and methods: Eleven patients (30.2 ± 12.3 months after transplantation) receiving immunosuppressive therapy consisting of cyclosporin A, prednisone and azathioprine with LDL cholesterol (LDL-C) concentrations exceeding 3.9 mmol/l and 8 control subjects were included into the study. In addition to the immunosuppressive therapy, the patients received a daily dose of 40 mg/day pravastatin for the first 8 days which was then reduced to 10 mg/day administered until Day 29. Blood was sampled for pharmacokinetic profiling (maximum concentration of the drug (C max ), time to reach C max (t max ), area under the concentration vs. time curve (AUC 0-24h ), elimination half-life time (t el )) and measurement of the parameters of clinical chemistry on Days 1, 8 and 29. The control group received a single dose of 60 mg pravastatin and the values of C max and AUC 0-24h were normalized for a dose of 10 mg. Results: Pravastatin 40 mg/day for 1 week in the patient group caused a significant reduction in total cholesterol (C) and LDL-C from 8.11 ± 1.20 mmol/l and 5.88 ± 1.15 mmol/l to 6.91 ± 1.01 mmol/l and 4.72 ± 1.05 mmol/l, respectively (p = 0.005 and p = 0.003). Triglycerides and HDL cholesterol (HDL-C) concentrations did not change significantly. Mean values for C max of pravastatin were 384.2 ng/ml, 392.0 ng/ml and 115.1 ng/ml in patients on Days 1, 8 and 29, respectively. After normalization for a dose of 10 mg, the corresponding values of C max-DN10mg and C max were 96.0 ng/ml, 98.0 ng/ml and 115.1 ng/ml on study Days 1, 8 and 29. These values were 7 - 8 times higher than the normalized value of C max-DN10mg for the control group (13.7 ng/ml). The corresponding values of AUC 0-24h were 1228.2 ng/ml×h, 1214.1 ng/ml×h and 345.9 ng/mlxh in the patient group on study Days 1, 8 and 29 as well as 157.5 ng/ml×h in the control group prior to normalization. After normalization for a dose of 10 mg, the values of AUC 0-24-DN10mg in the patient group were approximately 12 times higher than those of the control group. However, no significant differences between the 2 groups were observed in t max and t el . Within the patient group, no significant increase in C max or AUC was found on Day 1 to Day 8. The results of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) showed also no significant increase during the observation period.