Exposure-response analysis of pregabalin add-on treatment of patients with refractory partial seizures.
OBJECTIVE
Our objectives were to describe the exposure-response relationship of pregabalin add-on treatment for refractory partial seizures after multiple dosing in patients and to identify the factors that influence this relationship.


METHODS
A mixed-effects model was used to characterize the relationship between monthly seizure frequency over a 3-month period and pregabalin daily dose (0, 50, 150, 300, and 600 mg) as add-on treatment in 3 double-blind, parallel-group studies in patients with refractory partial seizures (N = 1042). Seizure frequency was modeled as a Poisson process expressed as a function of baseline seizures, drug treatment, placebo effect, and subject-specific random effects. The model included a parameter that partitioned the population into subpopulations with respect to response.


RESULTS
Seventy-five percent of patients showed an asymptotic decrease in seizure frequency with increasing doses of pregabalin, whereas 25% did not demonstrate a significant decrease in seizure frequency from baseline. In patients who demonstrated a dose-related decrease in seizure frequency from baseline, the maximal percentage of seizure reduction from baseline was 100% for women and 80% for men, with a 186-mg daily dose decreasing seizures on average to 50% of maximum. Age, race, and menopausal status did not significantly affect seizure frequency.


CONCLUSIONS
Pregabalin add-on treatment demonstrates a dose-response relationship in 3 out of 4 patients with refractory partial seizures. A dose of 186 mg pregabalin daily is expected to decrease the seizure rate by 50% of maximum from baseline. Age, race, and menopausal status of women did not affect the dose-response relationship.
Miller
Raymond
R
Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Frame
Bill
B
Corrigan
Brian
B
Burger
Paula
P
Bockbrader
Howard
H
Garofalo
Elizabeth
E
Lalonde
Richard
R
D000328:Adult; D000465:Algorithms; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D016012:Poisson Distribution; D011153:Population; D000069583:Pregabalin; D012107:Research Design; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid