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MSc student, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
Medical Director, Renal Transplantation and Medical Manager, Solid Organ Transplantation, Vancouver General Hospital; Clinical Associate Professor, Faculty of Medicine, University of British Columbia
Clinical Coordinator & Pharmacotherapeutic Specialist (Transplant/Immunology), Vancouver Coastal Health Authority; Clinical Professor, Faculty of Pharmaceutical Sciences, University of British Columbia
PhD candidate, Faculty of Pharmaceutical Sciences, University of British Columbia; now, Senior Scientist, Clinical PK/PD DMPK, Translational Sciences, Novartis Pharmaceuticals Corporation, East Hanover, NJ
Professor, Faculty of Pharmaceutical Sciences, University of British Columbia
Professor and Director, Doctor of Pharmacy Program, Faculty of Pharmaceutical Sciences; Distinguished University Scholar, University of British Columbia; Clinical Pharmacy Specialist, Children's and Women's Health Centre of British Columbia, Vancouver
Reprints: Dr. Ensom, Department of Pharmacy (0B7), Children's & Women's Health Centre of British Columbia, 4500 Oak St., Vancouver, BC V6H 3N1, Canada, fax 604/875-3735, ensom{at}interchange.ubc.ca
BACKGROUND: Mycophenolate mofetil is widely used in islet transplant recipients and its active metabolite, mycophenolic acid (MPA), exhibits wide pharmacokinetic variability. However, to our knowledge, no limited sampling strategy (LSS) exists for monitoring MPA in this subpopulation.
OBJECTIVE: To define optimal LSSs for MPA monitoring and to test their predictive performance in islet transplant recipients.
METHODS: After written informed consent was obtained and upon administration of a steady-state morning mycophenolate mofetil dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours from 16 stable islet transplant recipients. MPA concentrations were measured by a validated high-performance liquid chromatography method with ultraviolet detection and pharmacokinetic parameters analyzed by noncompartmental modeling. All 16 patients' profiles were used to develop the LSSs via multiple regression analysis. Potential LSSs were restricted to ones having R2 0.90 or greater and 3 or fewer time points within the first 4 hours postdose. Resulting equations were validated for their predictive performance using the jackknife method, with acceptable criteria for bias and precision preset to within ±15%. In addition, 14 published LSSs (in the renal transplant population) were tested in our islet transplant patients.
RESULTS: Five LSSs met preset criteria and had conventional sampling times:
where AUC = area under the concentration-time curve. None of the other published LSSs in the renal transplant population met the preset criteria for bias and precision.
CONCLUSIONS: To our knowledge, these are the first precise and accurate LSSs for predicting MPA AUC developed specifically for islet transplant recipients. The LSS that we recommend is the one utilizing 2 concentrations: AUC = 1.547 + 1.417C1 + 9.448C4. This equation is convenient and clinically feasible. Other islet transplant centers may wish to validate our equation in their population or use our template as a guide to develop accurate and precise LSSs specific to their patient population.
Key Words: islet transplant, limited sampling strategy, mycophenolic acid, therapeutic drug monitoring
Published Online, December 8, 2009. www.theannals.com, DOI 10.1345/aph.1M511
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