licon dioxide, dibasic calcium phosphate dihydrate, glyceryl behenate, magnesium stearate, sodium lauryl sulfate, and talc.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionGabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS and PHN are attributable to gabapentin.
The precise mechanism by which gabapentin is efficacious in RLS and PHN is unknown.
The mechanism of action by which gabapentin is efficacious in PHN is unknown but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and mice (e.g., spinal nerve ligation models, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test), but does not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to human pain is not known.
Gabapentin is structurally related to the neurotransmitter gamma aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil and gabapentin have been tested in radioligand binding assays, and neither exhibited affinity for a number of other common receptor, ion channel, or transporter proteins.
In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin enacarbil in RLS and PHN is unknown.
12.3 PharmacokineticsHORIZANT is an extended-release formulation of gabapentin enacarbil, a prodrug of gabapentin. HORIZANT provides approximately dose-proportional and extended exposure to gabapentin over the range 300 to 6,000 mg. HORIZANT and gabapentin are not interchangeable because the same daily dose of each results in different plasma concentrations of gabapentin.
For subjects with PHN taking HORIZANT 600 mg twice daily, the estimated steady state mean Cmax was 5.35 µg/mL, mean AUC24 was approximately 109 µg*hr/mL, mean Cmin was 3.63 µg/mL, and mean peak trough ratio was 1.5.
Absorption: The pathway for absorption of gabapentin enacarbil is believed to include active transport via a proton-linked monocarboxylate transporter, MCT-1. This transporter is expressed at high levels in the intestinal tract and is not saturated by administration of high doses of HORIZANT. Mean bioavailability of gabapentin (based on urinary recovery of gabapentin) for HORIZANT in the fed state is about 75%. Bioavailability under fasting conditions has been estimated by gabapentin urinary recovery to be 42% to 65%. In a food effect study, the exposure of gabapentin increased by 24%, 34%, and 44% with low, moderate, and high fat meals, respectively. The Tmax of gabapentin after administration of 600 mg of HORIZANT was 5.0 hours in fasted subjects and 7.3 hours in fed subjects. Steady state is reached in 2 days with daily administration.
Distribution: Plasma protein binding of gabapentin has been reported to be <3%. The apparent volume of distribution of gabapentin in subjects receiving HORIZANT is 76 L.
Metabolism: After oral administration, gabapentin enacarbil undergoes ext |
