Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin.
OBJECTIVE
The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers.


BACKGROUND
LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process.


METHODS
As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio.


RESULTS
Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero.


CONCLUSIONS
Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.
Anderson
Gail D
GD
Department of Pharmacy, University of Washington, Seattle, USA.
Gidal
Barry E
BE
Messenheimer
John A
JA
Gilliam
Frank G
FG
D000293:Adolescent; D000328:Adult; D000368:Aged; D002220:Carbamazepine / Q000097:blood* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D010672:Phenytoin / Q000097:blood* / Q000627:therapeutic use; D012189:Retrospective Studies; D013375:Substance Withdrawal Syndrome / Q000097:blood*; D014227:Triazines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
D014227:Triazines; D002220:Carbamazepine; D010672:Phenytoin; D000077213:Lamotrigine