Clinical pharmacokinetics of tacrolimus in Asian liver transplant patients

Ph.DDOCTOR OF PHILOSOPH

Population Pharmacokinetics of Mycophenolic Acid and Metabolites in Patients With Glomerulonephritis

Mycophenolic acid (MPA) is an inosine monophosphate dehydrogenase inhibitor used for glomerulonephritis treatment. The objective of the current study was to develop a population pharmacokinetic model for MPA and metabolites in glomerulonephritis in order to enable appropriate design of MPA regimens in these patients with alterations in kidney structure and function

Population pharmacokinetics of mycophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients

The population pharmacokinetics of mycophenolic acid (MPA) and its phenolic (MPAG) and acyl (AcMPAG) glucuronide metabolites were studied in patients taking enteric-coated mycophenolate sodium. Plasma samples (n = 232), obtained from 18 renal transplant recipients, were analyzed for MPA, MPAG, and AcMPAG using a validated high-performance liquid chromatography/ultraviolet assay. Population pharmacokinetic analysis was performed using NONMEM. The pharmacokinetics of MPA were best described by a 2-compartment model, with MPAG and AcMPAG produced from the central compartment and with enterohepatic recirculation of MPA via these 2 metabolites. Population mean estimates for MPA were apparent clearance (CL/F) of 10.6 L/h (interindividual variability [IIV] = 21.4%) and apparent volume of distribution of the central compartment (V 1/F) of 25.9 L (IIV = 87.8%). Mean elimination rate constants of MPAG and AcMPAG were 0.323 h- 1 (IIV = 29.1%) and 0.206 h-1 (IIV = 48.8%), respectively. The mean fraction of MPA converted to MPAG and AcMPAG, normalized by their volumes of distribution (FMAG and FM AC, respectively), was also estimated. The elimination rate constant for MPAG and FMAC was influenced by glomerular filtration rate in patients with renal impairment. The visual predictive check, based on 100 simulated data sets each for MPA, MPAG, and AcMPAG, found that the final pharmacokinetic model adequately predicts the observed concentrations of all 3 species. © 2009 the American College of Clinical Pharmacology

Diabetes mellitus reduces the clearance of atorvastatin lactone: Results of a population pharmacokinetic analysis in renal transplant recipients and in vitro studies using human liver microsomes

Background and Objective: Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. Subjects and Methods: A total of 312 plasma concentrations of atorvastatin acid and atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis. Nonlinear mixed-effects modelling was employed to determine the population pharmacokinetic estimates for atorvastatin acid and atorvastatin lactone. In addition, the biotransformation of these compounds was studied using human liver microsomal fractions obtained from 12 nondiabetic and 12 diabetic donors. Results: In diabetic patients, the plasma concentration of atorvastatin lactone was significantly higher than that of atorvastatin acid throughout the 24-hour sampling period. The optimal population pharmacokinetic model for atorvastatin acid and atorvastatin lactone consisted of a two-and one-compartment model, respectively, with interconversion between atorvastatin acid and atorvastatin lactone. Parent drug was absorbed orally with a population estimate first-order absorption rate constant of 0.457 h-1. The population estimates of apparent oral clearance (CL/F) of atorvastatin acid to atorvastatin lactone, intercompartmental clearance (Q/F), apparent central compartment volume of distribution after oral administration (V1/F) and apparent peripheral compartment volume of distribution after oral administration (V2/F) for atorvastatin acid were 231 L/h, 315L/h, 325L and 4910 L, respectively. The population estimates of apparent total clearance of atorvastatin lactone (CLM/F), apparent intercompartmental clearance of atorvastatin lactone (QM/F) and apparent volume of distribution of atorvastatin lactone after oral administration (VM/F) were 85.4L/h, 166L/h and 249 L, respectively. The final covariate model indicated that the liver enzyme lactate dehydrogenase was related to CL/F and alanine aminotransferase (ALT) was related to Q/F. Importantly, diabetic patients have 3.56 times lower CL M/F than nondiabetic patients, indicating significantly lower clearance of atorvastatin lactone in these patients. Moreover, in a multivariate population pharmacokinetics model, diabetes status was the only significant covariate predicting the values of the CLM/F. Correspondingly, the concentration of atorvastatin acid remaining in the microsomal incubation was not significantly different between nondiabetic and diabetic liver samples, whereas the concentration of atorvastatin lactone was significantly higher in the samples from diabetic donors. In vitro studies, using recombinant enzymes, revealed that cytochrome P450 (CYP) 3A4 is the major CYP enzyme responsible for the biotransformation of atorvastatin lactone. Conclusions: These studies provide compelling evidence that the clearance of atorvastatin lactone is significantly reduced by diabetes, which leads to an increased concentration of this metabolite. This finding can be clinically valuable for diabetic transplant recipients who have additional co-morbidities and are on multiple medications. © 2012 Springer International Publishing AG. All rights reserved