Population pharmacokinetics of pregabalin in healthy subjects and patients with chronic pain or partial seizures.
OBJECTIVE
Pregabalin, a high-affinity ligand for α2δ subunits of voltage-gated calcium channels, is a novel pharmacotherapy for chronic pain, partial seizures, and other disorders. The present study investigated the population pharmacokinetics of pregabalin following single and multiple doses in healthy volunteers and patient populations.


METHODS
Using nonlinear mixed-effect modeling, 5,583 plasma pregabalin concentration-time samples from 1,723 subjects were analyzed: 2,868 samples from healthy volunteers or subjects with renal impairment (n = 123), 1,513 from patients with partial seizures (n = 626), and 1,202 from patients with chronic pain (n = 974). A one-compartment model with first-order elimination and absorption processes and absorption lag time was used.


RESULTS
This pharmacostatistical model showed that: (1) pregabalin oral clearance (CL/F) was directly proportional to creatinine clearance (CLcr), but was independent of gender, race, age, female hormonal status, daily dose, and dosing regimen; (2) apparent volume of distribution was dependent on body weight and gender; (3) absorption rate was decreased when given with food; and (4) coadministration with marketed antiepileptic drugs (AEDs) had no significant effect on pregabalin CL/F.


CONCLUSIONS
Pregabalin CL/F is related to CLcr, and this relationship is similar among healthy volunteers and patients with either partial seizures or chronic pain disorders. The only factor having a clinically significant influence on steady-state plasma pregabalin concentrations is renal function.
Neurosciences, Clinical Pharmacology, Pfizer Global Research & Development, New London, Connecticut 06320, USA. howard.bockbrader@pfizer.com
Howard N
HN
Bockbrader
Paula
P
Burger
Lloyd
L
Knapp
Brian W
BW
Corrigan
D000328:Adult; D000368:Aged; D000465:Algorithms; D000700:Analgesics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002908:Chronic Disease; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000378:metabolism*; D005006:Ethnicity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D011153:Population; D000069583:Pregabalin; D015203:Reproducibility of Results; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000700:Analgesics; D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid