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Mechanism of Action
The mechanism of action by which gabapentin exerts its analgesic action 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 formulin 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 GABA (gamma-aminobutyric acid), but it does not modify GABAa or GABAb radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. In radioligand binding assays at concentrations up to 100 ^M, gabapentin did not exhibit affinity for a number of other receptor sites, including benzodiazepine, glutamate, N- methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine- sensitive glycine; alpha 1, alpha 2, or beta adrenergic; adenosine A1 or A2; cholinergic, muscarinic, or nicotinic; dopamine D1 or D2; histamine H1; serotonin S1 or S2; opiate mu, delta, or kappa; cannabinoid 1; voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem; or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A20- alpha-benzoate. Gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin.
In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated. It is hypothesized that gabapentin antagonizes thrombospondin binding to a2S-1 as a receptor involved in excitatory synapse formation and suggested that gabapentin may function therapeutically by blocking new synapse formation.
No pharmacodynamic studies have been conducted with GRALISE.
Absorption and Bioavailability
Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases.
When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax and lower AUC at steady state compared to gabapentin immediate release (Table 5). Time to reach maximum plasma concentration (Tmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.
Table 5: Mean (SD) Steady-State Pharmacokinetics for
GRALISE and Gabapentin Immediate Release in Plasma of Healthy Subjects (Day 5,
n = 21)
|Pharmacokinetic Parameters (Mean ± SD)||GRALISE 1800 mg QD||Gabapentin Immediate Release 600 mg TID|
|AUC0-24 (ng • hr/mL)||132,808 ± 34,701||141,301 ± 29,759|
|Cmax (ng/mL)||9,585 ± 2,326||8,536 ± 1,715|
|Cmin (ng/mL)||1,842 ± 654||2,588 ± 783|
|Tmax (hr) median (range)||8 (3-12)||2 (1-5)*|
|* = relative to most recent dose|
Do not use GRALISE interchangeably with other gabapentin products because of differing pharmacokinetic profiles that affect frequency of administration.
GRALISE should be taken with evening meals. If it is taken on an empty stomach, the bioavailability will be substantially lower.
Administration of GRALISE with food increases the rate and extent of absorption of gabapentin compared to the fasted state. Cmax of gabapentin increases 33-84% and AUC of gabapentin increases 33-118% with food depending on the fat content of the meal. GRALISE should be taken with food.
Gabapentin is less than 3% bound to plasma proteins. After 150 mg intravenous administration, the mean ± SD volume of distribution is 58 ± 6 L.
Metabolism and Excretion
Gabapentin is eliminated by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. In patients with normal renal function given gabapentin immediate release 1200 to 3000 mg/day, the drug elimination half-life (t1/2) was 5 to 7 hours. Elimination kinetics do not change with dose level or multiple doses.
Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients and patients with impaired renal function, plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
Dosage adjustment in patients with compromised renal function is necessary. In patients undergoing hemodialysis, GRALISE should not be administered [see DOSAGE AND ADMINISTRATION].
As renal function decreases, renal and plasma clearances and the apparent elimination rate constant decrease, while Cmax and t1/2 increase.
In patients (N=60) with creatinine clearance of at least 60, 30 to 59, or less than 30 mL/min, the median renal clearance rates for a 400 mg single dose of gabapentin immediate release were 79, 36, and 11 mL/min, respectively, and the median t1/2 values were 9.2, 14, and 40 hours, respectively.
Dosage adjustment is necessary in patients with impaired renal function [see DOSAGE AND ADMINISTRATION].
In a study in anuric adult subjects (N=11), the apparent elimination halflife of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent halflife of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects. GRALISE should not be administered in patients undergoing hemodialysis. Alternative formulations of gabapentin products should be considered in patients undergoing hemodialysis.
Apparent oral and renal clearances of gabapentin decrease with increasing age, although this may be related to the decline in renal function with age. Reductions in gabapentin dose should be made in patients with age-related compromised renal function [see DOSAGE AND ADMINISTRATION].
Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment.
The pharmacokinetics of GRALISE have not been studied in patients less than 18 years of age.
Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.
Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.
The efficacy of GRALISE for the management of postherpetic neuralgia was established in a double-blind, placebo-controlled, multicenter study. This study enrolled patients between the age of 21 to 89 with postherpetic neuralgia persisting for at least 6 months following healing of herpes zoster rash and a minimum baseline pain intensity score of at least 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).
This 11-week study compared GRALISE 1800 mg once daily with placebo. A total of 221 and 231 patients were treated with GRALISE or placebo, respectively. The study treatment including titration for all patients comprised a 10-week treatment period followed by 1-week of dose tapering. Double-blind treatment began with titration starting at 300 mg/day and titrated up to a total daily dose of 1800 mg over 2 weeks, followed by 8 weeks fixed dosing at 1800 mg once daily, and then 1 week of dose tapering. During the 8-week stable dosing period, patients took 3 active or placebo tablets each night with the evening meal. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale. The mean baseline pain score was 6.6 and 6.5 for GRALISE and placebo-treated patients, respectively.
Treatment with GRALISE statistically significantly improved the endpoint mean pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 1: Percent of Patients Achieving Various Levels of
Last reviewed on RxList: 8/16/2012
This monograph has been modified to include the generic and brand name in many instances.
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