title: Apparent clearance of sirolimus in heart transplant recipients: impact of primary diagnosis and serum lipids.
abstract: The study was aimed to identify factors affecting sirolimus apparent clearance (CL/F) in de novo heart transplant recipients using a population pharmacokinetic approach. A total of 31 patients (7 female and 24 male) originally included in a formal clinical trial, contributed 524 sirolimus blood concentrations with the time after dose ranging from 11.08 to 31.83 hours. Sirolimus concentrations were measured using liquid chromatography-tandem mass spectrometry and data analysis was carried out using NONMEM (Globomax LLC, Hanover, MD) software. Factors screened included age, weight, gender, primary diagnosis, biochemical and hematological indices, cyclosporine dose, days post-transplant and potential interacting medications. The predictive performance of the final model was evaluated using a data-splitting method. Sirolimus apparent clearance (CL/F) was decreased by 20.8% for every 100 mg increase in cyclosporine daily dose and was 62.1% lower in patients with primary diagnosis of ischemic heart disease (IHD). Sirolimus apparent clearance was 37.8% lower when triglyceride was greater than 2 mmol/L. Based on the final model, the average values for sirolimus CL/F and apparent volume of distribution were 7.09 and 1350 L/h, respectively. Inter-subject variability in CL/F was 27.5% and residual random error was 24.1%. This study identified cyclosporine dose, hypertriglyceridemia and primary diagnosis of IHD as the most important factors affecting sirolimus CL/F. This information may assist in dose individualization of sirolimus in heart transplant recipients.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, 02881 RI, USA.
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: Anne
authors.initials: A
authors.lastname: Keogh
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D006207:Half-Life; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000097:blood / Q000628:therapy*; D020123:Sirolimus / Q000097:blood / Q000493:pharmacokinetics*; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D008055:Lipids; D014280:Triglycerides; D020123:Sirolimus