A Limited Sampling Model for Estimation of Total and Unbound Mycophenolic Acid (MPA) Area Under the Curve (AUC) in Hematopoietic Cell Transplantation (HCT)

Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Therapeutic Drug Monitoring (Impact Factor: 2.38). 06/2006; 28(3):394-401. DOI: 10.1097/01.ftd.0000211821.73231.8a
Source: PubMed


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 AUC0-12 in hematopoietic cell transplantation patients.
Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0-12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0-12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects.
Trough concentrations poorly estimate observed total and unbound AUC0-12 (r<0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0-12 after IV dosing (r>0.99). Oral total and unbound AUC0-12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r>0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0-12 predictions fell within +/-20% of the observed values without significant bias.
Trough MPA concentrations do not accurately describe MPA AUC0-12. 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 AUC0-12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0-12 targeting of MPA post hematopoietic cell transplantation.

25 Reads
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low high-density lipoprotein (HDL) cholesterol is a strong independent cardiovascular risk factor, which has been attributed to its role in reverse cholesterol transport. Whereas HDL also has potent antiinflammatory effects, the relevance of this property remains to be established in humans. In the present study, we evaluated whether there is a relation between HDL and sensitivity toward a low-dose endotoxin challenge. Thirteen healthy men with genetically determined isolated low HDL cholesterol (averaging 0.7+/-0.1 mmol/L) and 14 age- and body weight-matched healthy men with normal/high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with low-dose endotoxin intravenously (1 ng/kg body weight). The incidence and severity of endotoxin-associated clinical symptoms was increased in the low HDL group. Accordingly, both the inflammatory response (tumor necrosis factor-alpha, IL-1beta, IL-6, IL-8, and monocyte chemoattractant protein-1) as well as thrombin generation (prothrombin activation fragments F(1+2)) were significantly increased in the low HDL group on endotoxin challenge. Low HDL in healthy males is associated with increased sensitivity toward inflammatory stimuli as reflected by enhanced inflammatory and coagulation responses on endotoxin challenge. These antiinflammatory effects of HDL in humans may lend further support to HDL-increasing interventions, particularly in proinflammatory conditions, such as acute coronary syndromes.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2007; 27(5):1153-8. DOI:10.1161/ATVBAHA.106.136325 · 6.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycophenolate mofetil (MMF) is indicated as immunosuppressive therapy in liver transplantation. The abbreviated models for the estimation of mycophenolic acid (MPA) area under the concentration-time curve (AUC) have been established by limited sampling strategies (LSSs) in adult liver transplant recipients. In the current study, the performance of the abbreviated models to predict MPA exposure was validated in an independent group of patients. A total of 30 MPA pharmacokinetic profiles from 30 liver transplant recipients receiving MMF in combination with tacrolimus were used to compare 8 models' performance with a full 10 time-point MPA-AUC. Linear regression analysis and Bland-Altman analysis were used to compare the estimated MPA-AUC0-12h from each model against the measured MPA-AUC0-12h. A wide range of agreement was shown when estimated MPA-AUC0-12h was compared with measured MPA-AUC0-12h, and the range of coefficient of determination (r2) was from 0.479 to 0.936. The model based on MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h had the best ability to predict measured MPA-AUC0-12h, with the best coefficient of determination (r2=0.936), the excellent prediction bias (2.18%), the best prediction precision (5.11%), and the best prediction variation (2SD=+/-7.88 mg.h/L). However, the model based on MPA pharmacokinetic sampling time points C1h, C2h, and C4h was more suitable when concerned with clinical convenience, which had shorter sampling interval, an excellent coefficient of determination (r2=0.795), an excellent prediction bias (3.48%), an acceptable prediction precision (14.37%), and a good prediction variation (2SD=+/-13.23 mg.h/L). Measured MPA-AUC0-12h could be best predicted by using MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h. The model based on MPA pharmacokinetic parameters C1h, C2h, and C4h was more feasible in clinical application.
    Liver Transplantation 12/2007; 13(12):1684-93. DOI:10.1002/lt.21293 · 4.24 Impact Factor
Show more