Gerald Alter (Committee Member), Andrian Corbett (Committee Member), Jeffrey Gearhart (Committee Chair), James Lucot (Committee Co-chair), James Mcdougal (Committee Member)
Doctor of Philosophy (PhD)
Status epilepticus (SE) is a perplexing pathology involving a sudden and long disruption of the brain's normal electrical activity. The study of relevant cellular processes has been useful in identifying therapeutic targets. As a result, many novel drugs are being studied which target receptor systems involved in neuronal membrane excitability. Yet, the standard treatment for SE remains benzodiazepines (BZs), a class of GABAA agonist drugs. Unfortunately, the targeted receptors undergo a desensitization mechanism via enhanced endocytosis (receptor trafficking), leading to rapidly reduced BZ efficacy (pharmacoresistance) within minutes of seizure onset. A comprehensive understanding of the complex interplay between the anticonvulsant's pharmacokinetics and its effect during SE is still lacking. Quantitative information regarding how the trafficking mechanisms of the targeted receptor contribute to the drug's overall pharmacodynamic profile is especially important for the development and assessment of SE countermeasures. This is because the testing of seizure therapeutics can only be performed in animals. Therefore computational modeling of pharmacodynamics provides a useful approach for extrapolations to humans. This dissertation links a physiologically-based pharmacokinetic (PBPK) model for the therapeutic agent, with a cellular level pharmacodynamic (PD) model of the targeted receptors. The latter explicitly takes into accounts the targeted receptor's surface expression and disrupted trafficking during seizures and the binding of the therapeutic drug. This approach is demonstrated for the interaction of diazepam and its major active metabolite, with the GABAA receptor, the major therapeutic target. The GABAA receptor is known to be rapidly modulated during seizure activity. Hypothetically, by accounting for diazepam's pharmacokinetics and occupancy of BZ-sensitive GABAA receptors, as well as the cellular trafficking of those receptors during SE, one should be able to mathematically describe the rapid pharmacoresistance. The model developed suggests that approximately 55% occupancy of the original receptor number is required to reverse ongoing seizures. This is up from a reported 37% occupancy required to prevent seizures in the rat, when diazepam is administered just before seizure onset. The physiological basis of the model allows for extrapolation to humans and dose optimization. In addition, the modeling approach used may serve to explain why some drugs may be more or less effective than BZs in treating SE and to offer suggestions for alternative therapeutics.
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