Population Pharmacokinetic (PK) Analyses of Pregabalin (PGB) in Adult Patients with Refractory Partial Seizures.
Abstract number :
1.265
Submission category :
Year :
2001
Submission ID :
2973
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
H.N. Bockbrader, PhD, Clinical Pharmacokinetics, Pfizer, Inc, Ann Arbor, MI; P.J. Burger, BS, Development Operations, Pfizer, Inc, Ann Arbor, MI; B.W. Corrigan, PhD, Clinical Pharmacokinetics, Pfizer, Inc, Ann Arbor, MI; A.R. Kugler, PhD, Clinical Researc
RATIONALE: PGB, a novel antiepileptic drug (AED), has been studied as adjunctive therapy in patients with refractory partial seizures. The purpose of this meta-analysis is to investigate the population PKs of PGB in patients with partial seizures and assess the possible effect of concomitant AED therapy on PGB.
METHODS: Data collected from 5 Phase 1 studies (single and multiple-dose) with intense serial sampling and 4 Phase 2/3 studies with sparse sampling were used in the analysis. Single- (1- to 300-mg) and multiple- (75- to 900-mg/day [TID]) doses were administered in the Phase 1 studies (N=123 subjects) and multiple doses (50- to 600-mg/day [BID] and 150- to 600-mg/day [TID]) were administered in Phase 2/3 studies (N=626 subjects). Concentration-time data were modeled using NONMEM to estimate population PK parameters (mean and intersubject variability) as well as relationships between the mean PK parameters and various covariates.
RESULTS: Subjects were between the ages of 13-75 years. A 1-compartment model with first-order absorption and an absorption lag-time was used to characterize PGB PKs. PGB oral clearance (CL/F) was directly related to creatinine clearance (estimated by Cockcroft-Gault eq.). PGB CL/F was unaffected by subject status (healthy volunteer/patient), gender, race, menopausal status, daily dose, and dosing regimen. PGB CL/F was also unaffected by concomitant administration of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, or valproate. PGB distribution volume was dependent on subject weight and gender and the rate of PGB absorption was decreased when taken with meals.
CONCLUSIONS: The only factor to have clinically significant impact on PGB CL/F was renal function. This is consistent with the negligible metabolism of PGB and renal excretion as the predominant elimination pathway of PGB in humans. Steady-state plasma PGB concentrations were unaffected by concomitant administration of commonly prescribed AEDs.
Support: Pfizer Global Research and Development.
Disclosure: Salary - Pfizer, Inc.; Stock - Pfizer, Inc.