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Population pharmacokinetic-pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2014 Nov; Vol. 78 (5), pp. 1102-12. - Publication Year :
- 2014
-
Abstract
- Aim: The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK-PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period.<br />Methods: A total of 214 MPA plasma concentrations-time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK-PD modelling. The PK-PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK-PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models.<br />Results: A two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h(-1) 70 kg(-1) ; Vc /F, 45.4 (29.6, 55.6) l; Vp /F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h(-1) ; Ka , 2.5 (1.45, 4.93) h(-1) . Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK-PD parameter estimates (and their 95% confidence intervals) were: E0 , 3.45 (2.61, 4.56) nmol h(-1) mg(-1) protein and EC50 , 1.73 (1.16, 3.01) mg l(-1) . Emax was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E0 ) compared with Caucasian patients (mean value 2.13 mg l(-1) vs. 3.86 mg l(-1) ).<br />Conclusion: An integrated population PK-PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK-PD guided therapeutic drug monitoring strategy.<br /> (© 2014 The British Pharmacological Society.)
- Subjects :
- Adolescent
Child
Child, Preschool
Dose-Response Relationship, Drug
Graft Rejection enzymology
Graft Rejection immunology
Graft Rejection prevention & control
Humans
Immunosuppressive Agents blood
Mycophenolic Acid blood
Predictive Value of Tests
Tissue Distribution
Young Adult
IMP Dehydrogenase antagonists & inhibitors
Immunosuppressive Agents pharmacokinetics
Immunosuppressive Agents pharmacology
Kidney Transplantation
Models, Biological
Mycophenolic Acid pharmacokinetics
Mycophenolic Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 78
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24837828
- Full Text :
- https://doi.org/10.1111/bcp.12426