Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine
Authors: Lal Ritu , Sukbuntherng Juthamas , Luo Wendy , Vicente Virna , Blumenthal Robin , Ho Judy , Cundy Kenneth C. 
Published: January 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Gabapentin enacarbil is a transported prodrug of gabapentin that provides sustained, dose‐proportional exposure to gabapentin by taking advantage of high‐capacity transport pathways expressed throughout the intestinal tract. This prodrug has shown efficacy in multiple clinical trials for the treatment of moderate‐to‐severe primary restless legs syndrome and could potentially represent the first non‐dopaminergic treatment for this important disease.WHAT THIS STUDY ADDS• Unlike gabapentin, gabapentin enacarbil is actively absorbed from the intestine by multiple pathways, including the monocarboxylate transporter type‐1 transporter (MCT‐1). Although drug interactions of gabapentin have been reported in the literature, the distinctly different absorption pathway of gabapentin enacarbil requires a separate evaluation of the potential for interaction with other substrates of MCT‐1. To achieve this, the pharmacokinetics of gabapentin enacarbil were examined in healthy adults when administered alone or in combination with naproxen, a known MCT‐1 substrate.• After absorption, gabapentin enacarbil is completely hydrolyzed to gabapentin, and the released gabapentin is excreted by renal elimination. Gabapentin is a substrate for the organic cation transporter type‐2 (OCT2) present in the kidney. To examine the potential for an elimination‐site drug interaction resulting from administration of the prodrug, the pharmacokinetics of gabapentin enacarbil were examined in healthy adults when administered alone or in combination with cimetidine, a known substrate of OCT2.AIMGabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose‐proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high‐capacity nutrient transporters, including mono‐carboxylate transporter‐1 (MCT‐1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug–drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT‐1 substrate) or cimetidine (an OCT2 substrate).METHODSSubjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination.RESULTSWhen gabapentin enacarbil was co‐administered with naproxen, gabapentinCss,maxincreased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co‐administered with cimetidine, gabapentin AUCssincreased by 24% and renal clearance of gabapentin decreased. Co‐administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated.CONCLUSIONSNo gabapentin enacarbil dose adjustment is needed with co‐administration of naproxen or cimetidine.