Population pharmacokinetics and pharmacodynamics of gabapentin after administration of gabapentin enacarbil.

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.

A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome.

OBJECTIVE: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). METHODS: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12. RESULTS: Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ~6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with "much improved"/"very much improved" Clinical Global Impression-Improvement scores (investigator and patient ratings) ranged from -12.9 to -13.9 for GEn treatment groups versus -9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. CONCLUSIONS: Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.

Evaluation of gabapentin enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. OBJECTIVE: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. METHODS: This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored. RESULTS: Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥ 1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT-concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). CONCLUSION: In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers.

BACKGROUND: Gabapentin enacarbil is an actively transported prodrug of gabapentin that provides predictable dose-proportional gabapentin exposure with high (> or =68%) oral bioavailability. OBJECTIVES: The aims of this study were to investigate the pharmacokinetics and tolerability of gabapentin enacarbil up to supratherapeutic doses and the effects of gabapentin enacarbil on cardiac repolarization in healthy volunteers, and to provide a dose reference for a future definitive QT/corrected QT (QTc) study. METHODS: This was a randomized-sequence, double-blind, placebo-controlled, single escalating-dose, crossover study of gabapentin enacarbil 600-mg extended-release tablets administered as a single oral dose of 2400, 3600, 4800, or 6000 mg or placebo, with a 1-week washout between administrations. Blood samples were collected over a period of 36 hours after administration and were analyzed using a validated method of liquid chromatography/tandem mass spec-trometry. Blood gabapentin enacarbil and gabapentin concentrations were analyzed using noncompartmental methods. Tolerability was assessed by monitoring adverse events (AEs) (using subject interview/reporting), laboratory parameters, vital sign measurements, and 12-lead electrocardiography (ECG). Holter ECG was also performed. RESULTS: Thirty-two healthy volunteers were included in the study (18 women, 14 men; mean [SD] age, 31.2 [11.4] years; body mass index, 24.9 [3.04] kg/m(2)). Gabapentin enacarbil was converted rapidly to gaba-pentin after absorption. Gabapentin exposure in blood was proportional to gabapentin enacarbil dose over the range of 2400 to 6000 mg (1250-3125 mg-equivalent gabapentin). Blood concentrations of intact gabapen-tin enacarbil were low and transient (< or =0.5% of the released gabapentin concentration at all doses). The most commonly reported AEs were dizziness and nausea (50% and 25% of subjects, respectively). All but 4 AEs were mild to moderate in intensity. Two subjects experienced treatment-emergent AEs rated as severe: psychomotor retardation, vertigo, and sedation (4800-mg dose) and somnolence (6000 mg). All treatment-emergent AEs resolved without medical intervention. No serious AEs were reported, and none of the AEs led to study withdrawal. There were no clinically significant changes in laboratory parameters, vital sign measurements, or ECG values; QTc intervals did not exceed 480 msec or change from baseline >30 msec at any gabapentin enacarbil dose. CONCLUSIONS: Gabapentin enacarbil was associated with dose-proportional gabapentin exposure at doses up to 6000 mg and was generally well tolerated in these healthy subjects. These findings support the use of 6000-mg gabapentin enacarbil in a definitive QT/QTc study.