Single‐Dose Pharmacokinetics and Effect of Food on the Bioavailability of Topiramate, A Novel Antiepileptic Drug

Abstract

Topiramate, a new antiepileptic drug effective in controlling partial-onset seizures, was administered to humans for the first time as single oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phase I safety and pharmacokinetic study. Model-independent pharmacokinetic data analysis was performed on plasma concentration and renal excretion data for topiramate. Maximum plasma concentrations (Cmax) were observed between 1.4 and 4.3 hours after administration. Mean values for plasma Cmax and area under the concentration-time curve (AUC) increased linearly with dose; however, a greater-than-proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes. Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Approximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportionally over the 200 mg to 1,200 mg dose range. Elimination half-life (t1/2) values calculated from plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and independent of dose. Intersubject variability was low for all parameters. Renal clearance was 13.9 mL/min, suggesting that renal tubular reabsorption may be prominently involved in the renal handling of topiramate. The elimination profile of topiramate indicated that longer sampling times are necessary in future studies to more accurately determine the t1/2. Food effect studies indicated a slight reduction in the rate (approximately 10% decrease in mean Cmax and mean tmax approximately 2 hours later) but not the extent of absorption when topiramate was given with food. Topiramate demonstrates a number of favorable pharmacokinetic features, including linear and predictable dose-concentration relationships, excretion mainly as unchanged drug by the kidney, a dose-independent t1/2, low intersubject variability in pharmacokinetic parameters, and lack of clinically significant effect of food on bioavailability.

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

“…It is unlikely that the TPM concentrations in subjects receiving TPM doses <200 mg/day would yield such concentrations. However, higher doses of TPM (≥800 mg/day; 400 mg b.i.d) are likely to yield peak and steady-state plasma levels in excess of concentrations (50 µM) where we see distinct CYP3A4 induction (14,15). Moreover, given the large interindividual variability in TPM pharmacokinetics, it is likely that some individuals, especially those with impaired renal function, may achieve such levels even at lower TPM doses.…”

“…In a cohort of 12 women with epilepsy receiving stable dosages of valproic acid (VPA) along with a combination norethindrone, 1 mg/ethinyl estradiol, 35-µg tablet, TPM administered at doses of 200 mg/day, 400 mg/day, and 800 mg/day caused a statistically significant dose-related increase in the mean oral serum clearance (CL/F was 14.7-33% higher) of ethinyl estradiol (2). The mean C max value for ethinyl estradiol decreased by [15][16][17][18][19][20][21][22][23][24][25].4%, and the area under the curve (AUC 0−24 ) decreased by 18-30% at the 200-to 800-mg/day dose level. The pharmacokinetics of norethindrone remained unchanged.…”

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

“…5). In humans, TPM achieves peak serum concentrations in 1-4 h after oral dosing, with CSF concentrations, and presumably brain concentrations, reflecting free plasma levels (20,21,23,30,32). Figure 5 shows the estimated human brain and CSF TPM concentrations with the first dose and daily doses.…”

“…The estimates are based on maximal plasma concentrations (20,21,32). A cerebrospinal fluid (CSF)/plasma TPM concentration ratio of 0.81 based on subdural microdialysis measurements of a patient receiving daily TPM therapy was used (23).…”

“…TPM is rapidly absorbed, with peak serum concentrations observed 1-4 h after ingestion (T max ) (20)(21)(22). The drug bioavailability is >80% and minimally affected by food.…”