Population Pharmacokinetics of Pregabalin Extended-Release in Healthy Volunteers and Patients With Postherpetic Neuralgia, Fibromyalgia, and Partial-Onset Seizures

Abstract

A population pharmacokinetic (PK) model was developed to characterize the properties of pregabalin extended-release (ER) in healthy volunteers and was subsequently applied to patient data from efficacy/safety studies investigating pregabalin ER for postherpetic neuralgia, fibromyalgia, and partial-onset seizures. The impact of demographic and other covariates on PK was assessed, and various dosing scenarios were simulated to inform pregabalin ER dosing/administration instructions. Phase 1 and 3 models were developed using data from 14 phase 1 studies (12 627 samples from 335 participants receiving pregabalin immediate-release [IR] or ER) and 3 phase 3 studies (2591 samples from 1235 patients receiving pregabalin ER), respectively. Final phase 1 and 3 models adequately characterized the data. Several covariates were statistically significant, but renal function (creatinine clearance) was considered the only clinically relevant covariate. The relationship between creatinine clearance and pregabalin clearance was reasonably consistent between phase 1 and 3 models and with that reported previously with pregabalin IR data alone. Patients with moderate renal impairment who received pregabalin ER 82.5 mg once daily (QD) had similar predicted area under the plasma concentration-time curve and peak plasma concentration values as patients with normal/mild renal impairment who received 165 mg QD. Ranges in predicted PK parameters after switching from pregabalin IR administered in the morning to ER after a meal at 3, 6, or 9 pm were similar. Administration of a missed evening dose at bedtime with food or the next morning with food did not result in clinically important changes in predicted PK parameters.

Keywords: epilepsy; fibromyalgia; pharmacokinetics; postherpetic neuralgia; pregabalin.