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Professor, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Clinical Pharmacy Specialist, Pharmacy Department, Children's & Women's Health Centre of British Columbia
Clinical Assistant Professor, Faculty of Pharmaceutical Sciences, University of British Columbia; Clinical Coordinator and Clinical Pharmacy Specialist, Pharmaceutical Sciences Clinical Services Unit, Vancouver General Hospital, Vancouver
Research Consultant, Children's & Women's Health Centre of British Columbia
Clinical Associate Professor, Department of Medicine, University of British Columbia; Transplant Cardiologist, Heart Transplant Program, St. Paul's Hospital, British Columbia Transplant Society, Vancouver
Associate Professor of Surgery, University of British Columbia; Surgical Director, Lung Transplant Program, British Columbia Transplant Society
Associate Professor of Medicine, University of British Columbia; Medical Director, Lung Transplant Program, British Columbia Transplant Society
Reprints: Mary HH Ensom PharmD FASHP FCCP FCSHP, Department of Pharmacy, 0B7, Children's & Women's Health Centre of British Columbia, 4500 Oak St., Vancouver, British Columbia V6H 3N1, Canada, FAX 604/875-3735, ensom{at}interchange.ubc.ca
BACKGROUND: The available pharmacokinetic and pharmacodynamic data on mycophenolic acid (MPA), the pharmacologically active metabolite of mycophenolate mofetil (MMF), are derived largely from renal transplant patients, not thoracic transplant recipients.
OBJECTIVE: To evaluate, in a pilot study, the pharmacokinetics of MPA at 3 different times in the early period (up to the first 9 mo) following lung or heart transplantation.
METHODS: Nine patients were entered into this open-label study. Upon administration of a steady-state morning MMF dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours after the dose at 3 times (denoted as sampling periods 1, 2, and 3) in the early posttransplant period. Total MPA concentrations were measured by a validated HPLC method with ultraviolet detection and followed by ultrafiltration of pooled samples for unbound MPA concentrations. Pharmacokinetic parameters (maximal concentration [Cmax], dose-normalized Cmax, time to Cmax, minimum concentration, predose concentration, AUC, dose-normalized AUC, free fraction, free AUC) were calculated by traditional noncompartmental methods.
RESULTS: Patient characteristics included 7 men and 2 women, 5 lung and 4 heart transplant recipients, mean ± SD age 53 ± 11 years, and weight 77 ± 14 kg. All patients were receiving prednisone and cyclosporine (with the exception of 2 pts. on tacrolimus during sampling periods 2 and 3). Sampling periods 1, 2, and 3 occurred on posttransplant days 15 ± 13, 56 ± 33, and 125 ± 73, respectively. No significant differences were found between sampling periods in any pharmacokinetic parameter. Drug exposure as evaluated by AUC was 39.95 ± 44.86, 25.24 ± 25.68, and 43.96 ± 38.67 µg•h/mL during sampling periods 1, 2, and 3, respectively, (p > 0.05).
CONCLUSIONS: As of September 26, 2003, this is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early posttransplant period. Wide interpatient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.
Key Words: mycophenolate, mycophenolate mofetil, mycophenolic acid, pharmacokinetics, transplantation
Published Online, October 10, 2003. www.theannals.com, DOI 10.1345/aph.1D099
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