Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Abstract

Summary:Purpose: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM.Methods: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day). Blood and urine samples were collected for ≥72 h after dosing. TPM and its metabolites were assayed in plasma and urine by a specific liquid chromatography-mass spectroscopy (LC-MS) method.Results: Mean TPM oral clearance (CL/F) increased from 1.2 L/h (control) to 2.2 L/h after CBZ treatment. Mean TPM halflife decreased from 29 h to 19 h. TPM was excreted extensively in urine both under noninduced (56%) and CBZ-induced conditions (40%). 2,3-O-Des-isopropylidene-TPM (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with a recovery accounting for 3.2% and 7.9% of the TPM dose under noninduced and induced conditions, respectively. Corresponding recovery values for 10-hydroxy-TPM (10-OH-TPM) were 1.2% and 1.8%, respectively. The control AUC metabolite /AUC drug ratio for 2,3-diol-TPM and 10-OH-TPM were 1.5% and 0.6%, and they increased by threefold and twofold, respectively, after CBZ treatment.Conclusions: TPM remains appreciably excreted unchanged in urine (41%) under CBZ-induced conditions, even though TPM CL/F increased by twofold. Although 2,3-diol-TPM and 10-OH-TPM were measured in unconjugated form, the significant increases in their AUC and urinary excretion are consistent with the twofold increase in TPM clearance. Key Words: Topiramate-CarbamazepinePharmacokinetics-Metabolism-Drug interaction-Enzyme induction-Healthy subjects.Topiramate (TPM) is a broad-spectrum secondgeneration antiepileptic drug (AED), which is approved for adjunctive therapy or monotherapy or both in >95 countries worldwide (1-4). It also is approved for use as migraine prophylaxis and is under evaluation as a potential treatment in a variety of other neurologic and psychiatric disorders (3).The pharmacokinetics of TPM has been investigated mostly under noninduced conditions and is characterized by linearity over the 100-to 800-mg/day dose range, a low oral clearance (22-36 ml/min), largely accounted for by renal clearance of unchanged drug (10-20 ml/min), and a relatively long half-life (19-25 h) (5-7). The absolute bioavailability of TPM is 81-95%, and it is not affected by food (8). Although TPM is not extensively metabolized when administered in monotherapy (fraction metabolized, <30%) (5,9), when TPM is administered with enzyme-inducing AEDs such as phenytoin and carbamazepine (CBZ), its oral clearance increases up to twofold, and its half-life is reduced by ∼50% (10-12). The magnitude of increase in total clearance implies that the formation clearance of metabolites produced via inducible pathways (P-450 oxidation or glucuronide conjugation or both) ca...

A Nonlinear Mixed Effects Modelling Analysis of Topiramate Pharmacokinetics in Patients with Epilepsy

“…21,23) Enzyme induction by carbamazepine is associated with an approximately 2 to 3-fold increase in topiramate metabolic clearance. 7,10,22,24) It is interesting to note that in some studies in patients taking carbamazepine, topiramate renal clearance was also found to be significantly increased. 10,22) In contrast to carbamazepine, drug interaction with phenobarbital is considered as minor.…”

“…4,7,10,[20][21][22][23][24] Carbamazepine significantly reduces topiramate concentration-to-dose ratio compared to topiramate monotherapy in both children and adults. 21,23) Enzyme induction by carbamazepine is associated with an approximately 2 to 3-fold increase in topiramate metabolic clearance.…”

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…References for drugs whose half-lives are altered in patients receiving liver enzyme inducers: felbamate [36], lamotrigine [37], oxcarbazepine [38], rufinamide [39], tiagabine [40], topiramate [41] and zonisamide [15]. b Half-life increases to 30–90 h during concomitant therapy with valproic acid (enzyme inhibitor).…”

“…Approximately 50% of the absorbed dose is metabolized by the liver, with an increase in metabolism seen in patients concomitantly receiving therapy with classic enzyme inducers. Enzyme inducers can decrease the serum half-life from 20–30 h to approximately 12 h [41,164]. Children generally eliminate topiramate faster than adults [14,165].…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…Approximately 50% of the absorbed dose is metabolized by the liver. Hepatic enzyme inducers can decrease the serum half-life of topiramate from 20-30 hr to approximately 12 hr (Britzi et al, 2005;Sachdeo et al, 1996). Children generally eliminate topiramate faster than adults (Perucca, 2006;Rosenfeld et al, 1999).…”