PMID- 19808136 OWN - NLM STAT- MEDLINE DCOM- 20091231 LR - 20221222 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 31 IP - 8 DP - 2009 Aug TI - Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers. PG - 1776-86 LID - 10.1016/j.clinthera.2009.07.026 [doi] AB - 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. FAU - Lal, Ritu AU - Lal R AD - XenoPort, Inc., Santa Clara, California 95051, USA. ritu.lal@xenoport.com FAU - Sukbuntherng, Juthamas AU - Sukbuntherng J FAU - Luo, Wendy AU - Luo W FAU - Chen, Dan AU - Chen D FAU - Vu, Amanda AU - Vu A FAU - Tovera, James AU - Tovera J FAU - Cundy, Kenneth C AU - Cundy KC LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid) RN - 0 (Analgesics) RN - 0 (Anticonvulsants) RN - 0 (Carbamates) RN - 0 (Delayed-Action Preparations) RN - 0 (Prodrugs) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM MH - Adolescent MH - Adult MH - Analgesics/administration & dosage/adverse effects/*pharmacokinetics MH - Anticonvulsants/administration & dosage/adverse effects/*pharmacokinetics MH - Biological Availability MH - Carbamates/administration & dosage/adverse effects/*pharmacokinetics MH - Chromatography, Liquid MH - Cross-Over Studies MH - Delayed-Action Preparations MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Electrocardiography/methods MH - Female MH - Humans MH - Male MH - Middle Aged MH - Prodrugs MH - Tandem Mass Spectrometry MH - Young Adult MH - gamma-Aminobutyric Acid/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics EDAT- 2009/10/08 06:00 MHDA- 2010/01/01 06:00 CRDT- 2009/10/08 06:00 PHST- 2009/06/23 00:00 [accepted] PHST- 2009/10/08 06:00 [entrez] PHST- 2009/10/08 06:00 [pubmed] PHST- 2010/01/01 06:00 [medline] AID - S0149-2918(09)00260-4 [pii] AID - 10.1016/j.clinthera.2009.07.026 [doi] PST - ppublish SO - Clin Ther. 2009 Aug;31(8):1776-86. doi: 10.1016/j.clinthera.2009.07.026.