Pharmacokinetics of Single-Dose Oral Pregabalin Administration in Normal Dogs
Pregabalin, an α2δ ligand of neuronal voltage-gated calcium channels, is currently used to treat epilepsy and neuropathic pain in humans. Based on experimental rodent models and human clinical trials, pregabalin may be a useful drug for both anticonvulsant and pain management in dogs. Nevertheless, pharmacokinetics studies have not been performed for pregabalin in this species. The objective of this study was to describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose (4 mg/Kg).
Six adult research dogs (Labrador Retriever and Greyhound mix) were used. All studies were approved by Cornell University's Institutional Animal Care and Use Committee (IACUC). All dogs, after jugular vein catheterization, were given a single oral dose of pregabalin (4 mg/kg). Blood samples were collected at: 0 (before drug administration), 15, 30, 60, 90, 120, 180, 240, 360, 480, 720, 1440 and 2160 minutes after drug administration. Plasma pregabalin concentration was measured by HPLC. Various pharmacokinetic variables were measured by a commercially available software applied to the plasma concentration-time data.
No obvious adverse effects associated with the oral administration of pregabalin were observed. In all dogs, except for one, plasma pregabalin remained within the therapeutic range (for seizures) in humans (2.8-8.2 μg/ml) between hour 1 and 8 after administration. The pharmacokinetic parameters studied were (mean±SD and range): area under the curve (AUC) = 78.2±14.5µg-h/ml (56.5-92.1µg-h/ml); absorption half-life (T1/2abs) = 0.48±0.33h (0.25-1.11h); elimination half-life (T1/2el) = 6.81±0.55h (6.21-7.40h); time over the presumed minimum effective concentration (T>2.8 µg/ml) = 10.83±2.48h (6.97-14.47h); maximum plasma concentration (Cmax) = 6.8±1.2µg/ml (4.6-7.9µg/ml); time for Cmax to occur (Tmax) = 1.9±1.1h (1.0-4.0h); volume of distribution (Vd) = 0.49±0.07L/Kg (0.43-0.59L/Kg); clearance (Cl) = 50.8±9.6ml/h/Kg (42.0-65.3ml/h/Kg); mean residence time (MRT) = 10.4±0.8h (9.1-11.3h). Values were predicted for steady state plasma levels using 8h or 12h dosing intervals respectively: (Cssmax) = 12.2±2.5µg/ml; 9.5±1.2µg/ml; (Cssmin) = 6.5±1.2µg/ml, 3.6±0.8µg/ml; (Cssave) = 8.9±1.7µg/ml, 6.5±1.2µg/ml.
In conclusion, in normal dogs, a 4 mg/Kg oral dose of pregabalin is well tolerated and achieves plasma drug concentrations within the therapeutic range reported to control seizures in people between hour 1 and 8 after administration. Based on the favorable pharmacokinetics and tolerability demonstrated for oral pregabalin in this study, further study of efficacy for the treatment of neuropathic pain and seizures is warranted.