Population pharmacokinetic−pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post‐transplant period. (November 2014)

• Record Type: Journal Article
• Authors: Dong, Min; Fukuda, Tsuyoshi; Cox, Shareen; de Vries, Marij T.; Hooper, David K.; Goebel, Jens; Vinks, Alexander A.
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 5(2014:Nov.)
• Page Start: 1102
• Page End: 1112
• Publication Date: 2014-11
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12426
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12426-sec-0001" sec-type="section"> <title>Aim</title> <p>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.</p> </sec> <sec id="bcp12426-sec-0002" sec-type="section"> <title>Methods</title> <p>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 (<italic>n</italic> = 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 <italic>post hoc</italic> 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.</p> </sec> <sec id="bcp12426-sec-0003" sec-type="section"> <title>Results</title> <p>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/<italic>F</italic>, 22 (14.8, 25.2) l h<sup>−1</sup> 70 kg<sup>−1</sup>; <italic>V</italic><sub>c</sub>/<italic>F</italic>, 45.4 (29.6, 55.6) l; <italic>V</italic><sub>p</sub>/<italic>F</italic>, 411 (152.6, 1472.6)l; Q/<italic>F</italic>, 22.4 (16.0, 32.5) l h<sup>−1</sup>; <italic>K</italic><sub>a</sub>, 2.5 (1.45, 4.93) h<sup>−1</sup>. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/<italic>F</italic>. A simplified inhibitory E<sub>max</sub> model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E<sub>0</sub>, 3.45 (2.61, 4.56) nmol h<sup>−1</sup> mg<sup>−1</sup> protein and E<italic>C</italic><sub>50</sub>, 1.73 (1.16, 3.01) mg l<sup>−1</sup>. E<sub>max</sub> was fixed to 0. There were two African‐American patients in our study cohorts and both had low IMPDH baseline activities (E<sub>0</sub>) compared with Caucasian patients (mean value 2.13 mg l<sup>−1</sup><italic>vs.</italic> 3.86 mg l<sup>−1</sup>).</p> </sec> <sec id="bcp12426-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>