title: Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy.
abstract: The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.
authors.affiliation: Department of Pharmaceutics, University of Washington, H-272 Health Sciences Building, Box 357610, Seattle, Washington 98195, USA. rhlevy@u.washington.edu
authors.forename: Rene H
authors.initials: RH
authors.lastname: Levy
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ragueneau-Majlessi
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Brodie
authors.forename: David F
authors.initials: DF
authors.lastname: Smith
authors.forename: Jaymin
authors.initials: J
authors.lastname: Shah
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Pan
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000077213:Lamotrigine; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D013997:Time Factors; D014227:Triazines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000078305:Zonisamide
chemical_list: D007555:Isoxazoles; D014227:Triazines; D000078305:Zonisamide; D000077213:Lamotrigine