Pregabalin Controlled-Release Pharmacokinetics in Healthy Volunteers: Analysis of Four Multiple-Dose Randomized Clinical Pharmacology Studies

Pregabalin (Lyrica®) is approved as an immediate-release (IR) formulation for administration twice (BID) or three times (TID) a day depending on indication. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience. The objectives of this analysis were: (1) to evaluate the pharmacokinetics of pregabalin controlled-release (CR) administered with food relative to the pregabalin IR formulation administered fasted; (2) to evaluate the pharmacokinetics of a two-tablet dose of pregabalin CR compared with the equivalent one-tablet dose of pregabalin CR; and (3) to determine the safety and tolerability of multiple-dose administration of pregabalin CR and IR. The pharmacokinetic properties of pregabalin CR were determined in four phase I, open-label, multiple-dose crossover studies (18–24 participants/study). Pregabalin CR (82.5, 165, 330 or 660 mg/day) administered QD was compared with pregabalin IR (75, 150, 300 or 600 mg/day, respectively) administered either BID or TID. Blood samples were collected up to 24 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. Eight-four healthy participants (19–55 years of age) received pregabalin. For all pregabalin CR doses, total exposure was equivalent to the corresponding pregabalin IR dose. Relative bioavailability of pregabalin CR was 93–97 % of pregabalin IR, and bioequivalence criteria with respect to the 24-h steady-state exposure (area under the plasma concentration–time curve from 0 to 24 h [AUC24]) were met. Administration of a two-tablet dose of pregabalin CR was bioequivalent to one-tablet pregabalin CR. The relative bioavailability of two-tablet pregabalin CR was 97–102 % of one-tablet pregabalin CR, and bioequivalence criteria with respect to AUC24 and peak plasma concentrations were met. Pregabalin CR pharmacokinetic parameters were dose proportional following administration of 82.5–660 mg/day pregabalin CR. Pregabalin was well tolerated across studies, with no serious or severe adverse events. Total daily exposure with multiple-dose pregabalin CR is equivalent to the corresponding pregabalin IR dose.