Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients.
BACKGROUND
The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction.


OBJECTIVE
To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients.


METHODS
Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection.


RESULTS
Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0-20.6%; 3018 vs 3290 ng.h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded.


CONCLUSIONS
Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.
Taylor
Paul J
PJ
Department of Medicine, University of Queensland, Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Kubler
Paul A
PA
Lynch
Stephen V
SV
Allen
Joan
J
Butler
Maree
M
Pillans
Peter I
PI
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D016572:Cyclosporine; D002784:Cholesterol; D000069059:Atorvastatin