Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine

Abstract

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. AIM Gabapentin 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). METHODS Subjects (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. RESULTS When gabapentin enacarbil was co‐administered with naproxen, gabapentin Css,max increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co‐administered with cimetidine, gabapentin AUCss increased 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. CONCLUSIONS No ...

Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use

“…In both cases, the interaction is due to competition for cellular transporters; the magnitude of these interactions, however, does not reach clinical significance [36].…”

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

“…The gastrointestinal toxicity Table 1 Intestinal Transporter- Targeted 119 Gabapentin Gabapentin enacarbil 122,123 Saquinavir (SQV) Biotin-SQV 124 derived from the parent drugs will also be easily reduced by such prodrug derivatization. It is concluded that SLC transportertargeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs such as low solubility and low permeability, though the possible suppressive effect of foods also should be taken into consideration.…”

“…In addition, transport by SMVT in oocytes and uptake studies in human embryonic kidney cells indicated that gabapentin enacarbil is a substrate for several high-capacity absorption pathways present throughout the intestine such as SMVT, including monocarboxylate transporter-1 (SLC16A1). 120,122 In rats, more than 95% of an oral dose of gabapentin enacarbil was excreted into urine within 24 h as gabapentin, indicating the high oral bioavailability of gabapentin via gabapentin enacarbil. In monkeys, oral bioavailability of gabapentine from gabapentin enacarbil capsules was 84.2% compared with 25.4% after a similar oral dose of gabapentin.…”

Gabapentin enacarbil – clinical efficacy in restless legs syndrome

“…The AUC values of gabapentin enacarbil, when co-administered in combination with naproxen or cimetidine, increased up to 12% and 24%, respectively. The results indicate that gabapentin enacarbil can be used together with MCT-1, organic cation transporter 2, or other transporter substrates without the need to alter the dose regimes 59,60…”