A nonlinear mixedeffects pharmacokinetic model co

Authors: William M Sallas Jerry R Nedelman Lewis B Sheiner John A Meligeni William T Robinson

Publish Date: 1995/11/21

Volume: 23, Issue: 5, Pages: 495-514

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Abstract

A nonlinear mixedeffects model simultaneously modeled two pharmacokinetic PK variables in patients administered cyclosporine twice daily i concentration of drug in blood at the end of the 12hr dosing interval C12 and ii area under the concentrationtime curve within the dosing interval AUC For two formulations Neoral® and Sandimmune® the model assessed the following nonlinearity with respect to dose interoccasion intraindividual variability interindividual variability and within and acrossindividual correlation betweenC12 andAUC Data were pooled from six clinical studies in stable renal transplant patients administered each formulation PK samples on two occasions were taken usually for each formulation Each individuals random effect was eightdimensional consisting of two PK variables for each formulation on two occasions An ANOVAlike partitioning worked well and reduced the variance matrix for the random effect to a known function of 13 parameters to be estimated thereby making a numerically intensive computation feasible Simulations were used to check the model fit to compute standard errors and to account for peculiarities in the residual analysis Outcomes of tests comparing formulations most of which were statistically significant favored Neoral® dose proportional lower interoccasion variability lower interindividual variability and higher correlation betweenC12 andAUC

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