期刊
THERAPEUTIC DRUG MONITORING
卷 28, 期 3, 页码 394-401出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.ftd.0000211821.73231.8a
关键词
mycophenolic acid; mycophenolate mofetil; limited sampling strategy; hematopoietic stem cell transplantation; pharmacokinetics
资金
- NCI NIH HHS [5K23CA096622, K23 CA096622] Funding Source: Medline
- NCRR NIH HHS [M01-RR00400] Funding Source: Medline
Objectives: Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC(0-12) in hematopoietic cell transplantation patients. Methods: Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil I g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC(0-12) was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC(0-12) models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects. Results: Trough concentrations poorly estimate observed total and unbound AUC(0-12) (r(2) < 0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC(0-12) after IV dosing (r(2) > 0.99). Oral total and unbound AUC(0-12) was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r(2) > 0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC(0-12) predictions fell within 20% of the observed values without significant bias. Conclusion: Trough MPA concentrations do not accurately describe MPA AUC(0-12). Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC(0-12) nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC(0-12) targeting of MPA post hematopoietic cell transplantation.
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