Pharmacokinetic-Pharmacodynamic Modeling of Intravenous and Oral Topiramate and Its Effect on the Symbol-Digit Modalities Test in Adult Healthy Volunteers

• Published in: Journal of clinical pharmacology 2016-06, Vol.56 (6), p.714-722
• Main Authors: Lim, Chay Ngee, Birnbaum, Angela K., Brundage, Richard C., Leppik, Ilo E., Cloyd, James C., Clark, Annie, Marino, Susan E.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Adult; Anticonvulsants; cognition; Cross-Over Studies; Double-Blind Method; Female; Fructose - administration & dosage; Fructose - analogs & derivatives; Fructose - pharmacokinetics; Healthy Volunteers; Humans; Male; Middle Aged; modeling; Models, Biological; Neuropsychological Tests; practice effect; Psychomotor Performance - drug effects; Psychomotor Performance - physiology; SDMT; topiramate; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.646

A sequential pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol‐Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19–55 years of age), using both oral and a novel stable‐labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration‐SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.