Pharmacokinetics of Pregabalin Controlled-Release in Healthy Volunteers: Effect of Food in Five Single-Dose, Randomized, Clinical Pharmacology Studies

Abstract

Background

The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food.

Objectives

This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food.

Methods

The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24–28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard noncompartmental methods. Adverse events were monitored throughout all studies.

Results

One hundred and twenty-eight healthy participants (19–54 years of age) received pregabalin. Peak plasma concentrations (C _max) were lower for CR than the respective pregabalin IR doses, and time to C _max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration–time curve from time zero extrapolated to infinite time (AUC_∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800–1,000 calorie medium-fat breakfast, AUC_∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75–86 %). When pregabalin CR was administered fasted, the AUC_∞ was 70–78 % of the AUC_∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC_∞ of the pregabalin CR formulation administered fasted was 62–69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported.

Conclusion

Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.