Effect of food and dose on pregabalin controlled release pharmacokinetics in healthy volunteers

Abstract

Pregabalin is indicated in the US for several conditions, including the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia or spinal cord injury, and fibromyalgia. It is currently approved as an immediate-release (IR) formulation with twice (BID) or three-times (TID) daily administration depending on indication. We report the pharmacokinetic results of seven Phase I open-label crossover studies (18-28 subjects/study) using a controlled-release (CR) once-daily formulation of pregabalin in healthy volunteers. Four multiple-dose studies analyzed the pharmacokinetics of 82.5, 165, 330 and 660mg (2x330mg) pregabalin CR taken once-daily following a medium-fat evening meal, compared with 25mg TID, 75mg BID, 150mg BID and 300mg BID pregabalin IR (fasted), respectively. For all CR doses, total pregabalin exposures (AUC24 [μg•h/mL]) were equivalent to the corresponding IR dose (as the ratio [CR/IR] of adjusted geometric means ranged from 93-97% and all the 90% CIs for AUC24 ratios fell entirely within the 80-125% acceptance range). Pregabalin CR pharmacokinetics were dose-proportional following administration of 82.5-660mg/day pregabalin CR. Three single-dose studies analyzed the effect of food on 330mg pregabalin CR pharmacokinetics compared with 300mg pregabalin IR. Neither fat nor calorie content of the preceding evening meal affected pregabalin CR pharmacokinetics compared with pregabalin IR. With food, total pregabalin exposures for 330mg CR were equivalent to 300mg IR (as the ratio [CR/IR] of adjusted geometric means ranged from 88-103% and the 90% CIs for AUCinf ratios fell entirely within 80-125%). Total exposure decreased by approximately 30% when pregabalin CR was administered under a fasting state in the evening or at bedtime. Pregabalin CR was well tolerated with no serious adverse events. Collectively, these seven studies demonstrate that, when administered following an evening meal, total daily exposure with pregabalin CR is equivalent to the corresponding pregabalin IR dose. Sponsored by Pfizer Inc.