Design of Drug Dosage Regimen for Valproate: Exploring Modeling and Simulation Based Approach

International Journal of Pharmacology and Clinical Sciences, 2014, 3, 2, 22-27.
Published: June 2014
Type: Research Article
Authors: Shiv sagar K, Nithya Duggirala, Chintan Y Patel, Leelavathy D Acharya, and Surulivelrajan Mallayasamy

Author(s) affiliations:
Shiv sagar K, Nithya Duggirala, Chintan Y Patel, Leelavathy D Acharya, Surulivelrajan Mallayasamy

Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Karnataka-576104, India.

Abstract

Background: Population pharmacokinetic studies attempt to explain the variability in pharmacokinetics among study subjects and explore the role of covariates on the pharmacokinetics. The present study was planned to evaluate by simulation, the various dosage regimens of valproate and their predicted relevance to achieve desired therapeutic ranges and to see the effect of various covariates. Materials and Methods: This study utilized the previous database of therapeutic drug monitoring data of valproate available in the department and population pharmacokinetic models developed by a group in the department. From the database, 93 patients’ details have been used in this study. The simulation studies were carried out for various dosage regimens such as 400mg Q12Hr, 500mg Q12Hr, 800mg Q12Hr, 1000mg Q24Hr for 100 simulated patients using NON-MEM software package. Results: 500mg BID dosage regimen was found to be more advantageous as more number of simulated patients were having the Css within the therapeutic range and the effect of covariates like sex and concomitant phenytoin use were found to be insignificant but with 1000mg OD regimen in females, the number of individuals with Css within the therapeutic range were found to be less with which we could say that the induction effect of phenytoin on valproate metabolism in females could be more than that of males. Conclusion: The present study was able to predict steady state concentrations for various dosage regimen scenarios with possible pharmacokinetic and therapeutic outcomes. This study underscores the relevance of population pharmacokinetic based simulations in dosage regimen design.

Keywords: Dosage regimen, NONMEM, Population pharmacokinetics, Simulations, Valproate

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