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DRUG INTERACTIONS

Effect of Atorvastatin on Cyclosporine Pharmacokinetics in Liver Transplant Recipients

Senior Scientist, Department of Medicine, University of Queensland, Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

Paul A Kubler, FRACP

Registrar, Department of Clinical Pharmacology, Princess Alexandra Hospital

Stephen V Lynch, FRACS

Associate Professor of Surgery, Department of Surgery, University of Queensland, Princess Alexandra Hospital

Joan Allen, RN

Nurse Practice Coordinator—Transplant Services, Princess Alexandra Hospital

Maree Butler, RN

Clinical Nurse, Liver Transplant Recipient Coordinator, Queensland Liver Transplant Service, Princess Alexandra Hospital

Peter I Pillans, FRACP

Director, Department of Clinical Pharmacology, Princess Alexandra Hospital; Senior Lecturer, Department of Medicine, University of Queensland, Princess Alexandra Hospital

Reprints: Peter I Pillans FRACP, Department of Clinical Pharmacology, 5th Floor, Building One, Princess Alexandra Hospital, Ipswich Rd., Brisbane, Queensland 4102, Australia, fax 61 7 3240 7131, peter_pillans{at}health.qld.gov.au

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.

Key Words: atorvastatin, cyclosporine, liver transplantation

Published Online, December 19, 2003. www.theannals.com, DOI 10.1345/aph.1D388

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