Pharmacokinetic-pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers.
OBJECTIVE
The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).


METHODS
Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.


RESULTS
Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ~100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l(-1) increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.


CONCLUSIONS
This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Ghada F
GF
Ahmed
Susan E
SE
Marino
Richard C
RC
Brundage
Serguei V S
SV
Pakhomov
Ilo E
IE
Leppik
James C
JC
Cloyd
Annie
A
Clark
Angela K
AK
Birnbaum
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009483:Neuropsychological Tests; D013060:Speech / Q000187:drug effects*; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose
modelling; pharmacodynamics; pharmacokinetics; topiramate; verbal fluency