Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Dr. F. Douglas Boudinot

Second Advisor

Dr. William R. Garnett


Background. Clinicians are divided on dosing recommendations when a dose is delayed or missed. For a neuropsychiatric agent like valproic acid (VPA), rational dosing recommendations are of particular importance. VPA is subject to therapeutic monitoring using total concentrations. Due to non-linear binding of VPA to plasma proteins, current dose titration schemes for VPA are empirical. The objectives of this research were to 1- study the effect of missed/delayed doses on steady state concentrations of VPA and 2-design a nomogram that can be used for dose titration based on total VPA concentrations. Methods. 1- A simulation study was conducted to test for different poor compliance scenarios. The effect of missed doses was quantified and used to derive dosing recommendations. 2- A clinical study was carried out in healthy volunteers. Nine volunteers were administered 500, 750 and 1000 mg VPA in a dose escalation study. A nomogram was developed using in vitro plasma protein binding data in all volunteers and tested using dose escalation data. Several delayed/missed doses scenarios were tested in order to validate the simulation model. 3- A revised simulation model was developed using combined information from plasma protein binding and pharmacokinetic analysis of clinical study data. Results and Discussion. Simulation study: Dosing recommendations in the case of a missed or delayed dose are both formulation and dose dependent. Results from the clinical study validated the simulation model and the revised simulation model properly incorporated intra and inter individual variabilities. VPA nomogram: A one-site saturable binding model provided an adequate description of the binding of VPA to albumin. A dosing nomogram for VPA was constructed. To avoid the risk of achieving toxic concentrations, the dose should not be increased by more than 2 fold at a time. The nomogram should be used in conjunction with patient history and clinical response. Conclusions. This research provides dosing recommendations to the clinicians to counsel patients taking preparations of VPA in the event of a missed dose. The use and validation of VPA nomogram will foster the rational use of VPA for the treatment of epilepsy and its role in other neuropsychiatric disorders.


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