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Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.

Abstract：

PURPOSE:Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability. METHODS:This randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs. FINDINGS:Of the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens. IMPLICATIONS:No significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.

journal_name

Clin Ther

journal_title

Clinical therapeutics

authors

Chen C,Upward J,Arumugham T,Stier B,Davy M

doi

10.1016/j.clinthera.2014.10.015

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

349-57

issue

eissn

0149-2918

issn

1879-114X

pii

S0149-2918(14)00688-2

journal_volume

pub_type

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Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.