A phase I, single-dose study of the disposition of 14C-radiolabeled gabapentin enacarbil in healthy male volunteers.
Gabapentin enacarbil (GEn) is a prodrug of gabapentin that is effective in restless legs syndrome (RLS) and has dose-proportional gabapentin exposure.


OBJECTIVE
This Phase I, open-label, non-randomized, single-center study of 14C-GEn in healthy male volunteers (XenoPort, Inc. protocol: XP065) characterized the mass balance, absorption, metabolism, and elimination pathways of GEn after oral administration of 14C-GEn.


METHODS
Subjects received GEn 600 mg as two gelatin capsules containing 300 mg immediate release GEn solution each with approximately 50 µCi of 14C-GEn. Pharmacokinetic assessments included total radioactivity excreted in urine (Aeu(0-t)) and feces (Aef(0-t)), mean maximum concentration (Cmax), 14C-GEn-derived radioactivity in plasma and whole blood, and gabapentin area under the concentration-time curve extrapolated to infinity (AUC0-inf). Tolerability was assessed using adverse events (AEs), vital signs, clinical laboratory tests, and ECGs. Six male subjects aged 24 - 46 years were recruited to the study.


RESULTS
Mean total recovery of 14C-GEn-derived radioactivity was 99.3% (94.1% in urine and 5.2% in feces). Mean Cmax and AUC for GEn-derived total radioactivity were similar in whole blood and plasma; the blood to plasma ratio for 14C-GEn-derived total radioactivity was 0.91. 14C-gabapentin was the only radioactive species present in blood. More than 85% of the radioactive dose was recovered in urine within 24 h of dosing. Eight treatment-emergent AEs were reported by 3 subjects; all were mild in intensity. There were no clinically relevant changes in vital signs, laboratory values, or ECGs.


CONCLUSIONS
GEn was extensively absorbed and rapidly eliminated from plasma and whole blood.
XenoPort, Inc., Santa Clara, CA, USA. ritu.lal@xenoport.com
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D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D002219:Carbamates; D002250:Carbon Radioisotopes; D005680:gamma-Aminobutyric Acid