期刊
JOURNAL OF CLINICAL PHARMACOLOGY
卷 52, 期 11, 页码 1654-1664出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0091270011429567
关键词
Mycophenolic acid; population pharmacokinetics; limited sampling schedule; hematopoietic cell transplantation
资金
- National Institutes of Health: National Heart, Lung, and Blood Institute [HL91744, HL36444]
- National Cancer Institute [CA15704, 18029, 78902]
- National Institute of Biomedical Imaging and Bioengineering [EB001975]
Mycophenolate mofetil (MMF) is a key component of post-grafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12) h for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8 h) for Q8-hour dosing.
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