Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study).
OBJECTIVE
To compare the pharmacokinetics (PK) of lamotrigine (LTG) when converting from twice-daily immediate-release (LTG-IR) to once-daily extended-release (LTG-XR) in subjects with epilepsy.


METHODS
An open-label, conversion study was conducted, consisting of a 2-week LTG-IR Baseline Phase, followed by a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Phase. Forty-four subjects (> or =13 years of age) were enrolled and grouped as metabolically neutral (15), induced (15), or inhibited (14) based on the effects of the concomitant antiepileptic drugs (AEDs) on the clearance of LTG. The primary outcome was LTG PK parameters upon conversion. Secondary outcomes included seizure frequency, adverse events, and subject's preference.


RESULTS
LTG-XR and LTG-IR regimens were similar with respect to area under curve from 0 to 24 h (AUC (0-24)), apart from the induced group, where the AUC (0-24) of LTG-XR was on average 21% lower than for LTG-IR. A reduction in the LTG Cmax was observed for LTG-XR compared to LTG-IR resulting in a decrease in the peak-to-trough fluctuation in serum LTG concentrations. The steady-state, dose-normalized, trough concentrations for LTG-XR were similar to those of LTG-IR. The median time to peak concentration (Tmax) following administration of LTG-XR ranged from 4 to 6 h, 6 to 10 h, and 9 to 11 h in the induced, neutral, and inhibited groups, respectively. In comparison, the median Tmax following administration of LTG-IR was between 1 and 1.5 h.


CONCLUSIONS
Trough concentrations of LTG can be maintained on conversion from twice-daily LTG-IR to once-daily LTG-XR at the same total daily dose.
Tompson
Debra J
DJ
GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, United Kingdom. debra.j.tompson@GSK.com
Ali
Imran
I
Oliver-Willwong
Ruth
R
Job
Sarah
S
Zhu
Li
L
Lemme
Francesca
F
Hammer
Anne E
AE
Vuong
Alain
A
Messenheimer
John A
JA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003692:Delayed-Action Preparations; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D000077213:Lamotrigine; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014839:Vomiting / Q000139:chemically induced