Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy.
OBJECTIVE
We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ).


METHODS
We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300-800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at approximately 2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy.


RESULTS
Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC(0-12)), Cmin(0), and Cavg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC(0-12), Cmax, Cmin(0), and Cavg values were approximately 40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered.


CONCLUSIONS
When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.
Sachdeo
R C
RC
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903-0019, USA.
Sachdeo
S K
SK
Walker
S A
SA
Kramer
L D
LD
Nayak
R K
RK
Doose
D R
DR
D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D000077236:Topiramate; D016896:Treatment Outcome
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; C012227:carbamazepine epoxide