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

Abstract

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.

Significant predictors for topiramate pharmacokinetics: a systematic review of population pharmacokinetic studies

“…Most studies were conducted in epilepsy patients in various age groups including infants, 24 infants and children, 19 children and adults, 25,26 and children, adults and elderly 21 . Moreover, three were conducted solely in adults with epilepsy, 18,20,22 and two studies in healthy volunteers 23,27 . The number of subjects and the number of observations varied across studies, ranging from 22 to 1217 and 118 to 4640, respectively.…”

“…All studies used NONMEM software for model development, with various estimation methods (Table 3). For the structural model development, six studies used a linear one‐compartment structure, 18,19,22,24–26 while three studies reported a two‐compartment linear model 20,21,27 and the other one used an E max model to describe the effects of single‐dose TPM on working memory, attention and psychomotor speed 23 . This model is commonly used to explain the concentration–effect relationship, in which E max is the maximal effect when all the receptors are occupied by the drug.…”

“…Other significant covariates included age, 21,26 renal function 18,22 and TPM daily dose 18 . As for the V D , weight, 18,19,22,24–27 age 19 and a baseline Symbol Digit Modalities Test (SDMT) score of the E max model 23 were significant predictors. The SDMT is a tool used to assess neurological dysfunction by identifying nine different symbols corresponding to the numbers 1–9.…”

“…Nonetheless, this study was conducted in healthy volunteers with TPM concentrations ranging from 0.05–3 mg/L, therefore, the applicability of these results to patients with epilepsy should be further investigated. The effects of 100 or 200 mg single dose TPM on working memory, attention and psychomotor speed were also investigated using SDMT 23 . The relationship between TPM concentrations and SDMT score was well described using an inhibitory E max model.…”

Topiramate in Migraine Prevention: A 2016 Perspective

“…vs IR topiramate b.i.d., but plasma concentration fluctuations may impact signature adverse cognitive effects such as word‐finding difficulty and psychomotor slowing. The occurrence and severity of these and other CNS AEs associated with topiramate are influenced by dose, rate of dose escalation, and plasma topiramate concentrations . Given this PK‐PD relationship, a bioequivalence study comparing an XR formulation (Trokendi XR q.d.)…”