Characterization of the Relationship Between Whole Blood and Plasma Topiramate Concentrations

University of Minnesota Ph.D. dissertation. August 2015. Major: Experimental & Clinical Pharmacology. Advisor: James Cloyd. 1 computer file (PDF); viii, 167 pages.The overall goal of my thesis was to determine the feasibility of dried blood spots (DBS) technology for measurement of topiramate (TPM) concentration and characterization of the relationship between whole blood and plasma TPM concentrations. Topiramate is widely used in the treatment of epilepsy and migraines and has shown to be effective in controlling seizures in children and adults. Topiramate has the potential to be a good therapy for neonatal seizures and Dravet’s syndrome. One major hurdle in developing drugs for treatment of childhood seizure disorders is the severe restriction on blood sampling in critically ill children, in whom blood is collected for a multitude of lab tests. This circumstance reduces the blood volume available for pharmacokinetics (PK) studies. Consequently, the necessary research on PK and dose finding is often significantly limited. The relationship between whole blood and plasma TPM concentrations were explored in canines with naturally-occurring epilepsy and adult and children on maintenance TPM therapy. In addition, the PK was described in both of these populations. In the canine study, four dogs were administered both intravenous (IV) and oral topiramate with the goal of comparing the PK of IV TPM in plasma and whole blood and describing the relationship between whole blood and plasma TPM concentrations. Similar to humans, the study showed a nonlinear relationship between plasma and whole blood TPM concentration in which whole blood TPM concentrations were 1.3-3.7 times greater than plasma concentrations. In addition, there was a difference in PK parameter estimates with those derived from whole blood generally showing reduced clearances resulting in longer elimination half-lives. In the adult and children study, thirty adult and eight children participants currently taking TPM therapy were recruited. These studies provide previously unreported information about TPM. Whole blood concentrations were found to be different than plasma concentrations with the whole blood TPM concentrations 0.9-4.4 times greater than plasma concentrations. These are the first studies comparing plasma and DBS TPM concentration obtained from patient samples using a formula that includes both hematocrit and the analyte-specific red blood cell-to-plasma ratio. The calculated TPM plasma concentration based on whole blood and DBS concentrations are in good agreement with analyzed plasma concentrations. Additionally, the PK of TPM was found to be similar to previous reported literature values. This thesis describes the development of bioanalytical assays to the implementation of these assays in clinical practice and clinical pharmacologic aspects of topiramate PK. Results from the studies described in this thesis provide a tool to estimate plasma concentrations from whole blood or DBS TPM concentrations. This will allow therapeutic drug monitoring using DBS and permit PK studies in populations where blood volume is limited