Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients.
OBJECTIVE
To determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy.


METHODS
This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for </=16 weeks, stable-dose TPM therapy combined with tapered-dose LTG therapy for 4 weeks, and stable-dose TPM monotherapy for 2 weeks. Serial blood and urine samples were collected before and during TPM dosing, and safety data were collected throughout the study.


RESULTS
The exposure, or area under the plasma LTG concentration-time curve within a dosing interval at steady state (AUCss), did not change in the presence of TPM, with mean AUCss values ranging at each TPM dose level between 66 and 81 mg x h/L with concomitant LTG/TPM therapy compared with 77 mgxh/L with LTG monotherapy. No significant change was found in the steady-state peak (Cmax) and trough (Cmin) plasma levels of LTG in the presence and absence of TPM. The mean (+/-SD) oral clearance (CL/F) of TPM (400 mg/day) was 2.6 +/- 1.1 L/h when given alone and 2.7 +/- 0.7 L/h when given with LTG. The similarity of CL/F values also was reflected by the similar exposure (AUCss), Cmax, and Cmin values of TPM in the absence, and presence of LTG.


CONCLUSIONS
The results of this study show that no PK interaction between TPM and LTGwas observed at the doses used in this study.
Doose
Dennis R
DR
Johnson & Johnson Pharmaceutical Research & Development L.L.C., Raritan, New Jersey, U.S.A. DDoose@prdus.jnj.com
Brodie
Martin J
MJ
Wilson
Elaine A
EA
Chadwick
David
D
Oxbury
John
J
Berry
David J
DJ
Schwabe
Stefan
S
Bialer
Meir
M
D000328:Adult; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D000077236:Topiramate; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D000077213:Lamotrigine