Tacrolimus and cerivastatin pharmacokinetics and adverse effects after single and multiple dosing with cerivastatin in renal transplant recipients.
OBJECTIVE
In contrast to cyclosporin, only limited information exists on the interaction potential between the immunosuppressive agent tacrolimus and HMG-CoA reductase inhibitors, which are metabolized via the cytochrome P450 system. The aim of this study was to investigate the pharmacokinetics, and adverse effects of cerivastatin combined with tacrolimus in renal transplant patients.


METHODS
Ten patients with stable kidney graft functions and LDL-cholesterol serum concentrations > 110 mg dl-1 were included in the study. After an observation period of 3 months, cerivastatin (0.2 mg daily) was administered for an additional 3 months. Tacrolimus steady-state pharmacokinetics and cerivastatin single- and multiple-dose pharmacokinetics were determined. Lipid concentrations, routine laboratory parameters and adverse events were obtained and analysed throughout the study period of 6 months.


RESULTS
Blood tacrolimus trough concentrations were not affected by cerivastatin (mean +/- SD 8.6 +/- 2.1 ng ml(-1) before, and 8.7 +/- 2.4 ng ml(-1) at day 90 of cerivastatin dosing, with a 95% confidence interval on the difference = 0.97, 1.08). The mean area under the blood concentration-time curve to 24 h (AUC(0,24 h)) for cerivastatin was 14.5 +/- 2.53 micro g l(-1) h(-1) at day 1 after starting treatment and 19.02 +/- 3.55 micro g l(-1) h(-1) (3 months later), resulting in a 35% higher (AUC(0,24 h)) compared with the first dose. Total cholesterol, LDL-cholesterol and triglyceride concentrations were significantly lowered by cerivastatin whereas no significant effect of cerivastatin on serum creatininkinase concentrations was observed and no adverse effects were documented.


CONCLUSIONS
Tacrolimus increased the AUC(0, 24 h) of cerivastatin by a mean of 35% in renal transplant patients. Cerivastatin had no detectable effect on the pharmacokinetics of tacrolimus.
Renders
Lutz
L
University Hospital of Schleswig-Holstein, Campus Kiel, Division of Nephrology, 24105 Kiel, Germany. renders@nephro.uni-kiel.de
Haas
Christian S
CS
Liebelt
Jan
J
Oberbarnscheidt
Martin
M
Schöcklmann
Harald O
HO
Kunzendorf
Ulrich
U
D000328:Adult; D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011725:Pyridines; C086276:cerivastatin; D016559:Tacrolimus