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Mechanism Of Action
Gabapentin 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.
HORIZANT 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.
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.
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.
After oral administration, gabapentin enacarbil undergoes extensive first-pass hydrolysis by non-specific carboxylesterases primarily in enterocytes and to a lesser extent in the liver, to form gabapentin, carbon dioxide, acetaldehyde, and isobutyric acid. Levels of gabapentin enacarbil in blood are low and transient ( ≤ 2% of corresponding gabapentin plasma levels). Released gabapentin is not appreciably metabolized in humans. Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Gabapentin enacarbil is neither a substrate nor an inhibitor of P-glycoprotein in vitro.
Following hydrolysis of gabapentin enacarbil, the released gabapentin is excreted unchanged by the kidney. Gabapentin renal excretion is believed to involve a component of active secretion via an organic cation transporter (OCT2) present in the kidney. In a human pharmacokinetic study with immediate release 14C gabapentin enacarbil, mean recovery of total radioactivity in urine was 94%, with 5% of the radioactive dose recovered in feces.
Apparent oral clearance (CL/F) of gabapentin from plasma after dosing of HORIZANT with food ranged from 6.0 to 9.3 L/hr. Following oral dosing of HORIZANT, plasma clearance of gabapentin is approximately proportional to creatinine clearance. Renal clearance (CLr) of gabapentin ranged from 5 to 7 L/hr, regardless of food intake or food type. The elimination half-life (t½) of gabapentin ranges from 5.1 to 6.0 hours and is unaltered by dose or following multiple doses of HORIZANT.
Race: In the population pharmacokinetic study, the majority (94%) of subjects in the clinical studies was Caucasian, and no single other race was greater than 4%; therefore, the effect of race could not be studied.
Gender: There are no clinically meaningful differences in pharmacokinetics of HORIZANT between male and female patients.
Geriatric Patients: There are no clinically significant differences in pharmacokinetics of HORIZANT between geriatric patients ( ≥ 65 years of age) and younger patients (18 to < 65 years of age). However, the pharmacokinetics in geriatric patients may be affected by an age-related decline in renal function [see Use In Specific Populations].
Renal Impairment: Gabapentin clearance after dosing with HORIZANT is approximately proportional to CrCl. Apparent oral clearance (CL/F) decreased in moderate (4.2 L/hr) and severe renal impairment patients (1.7 L/hr) compared with 6.0 to 9.3 L/hr in patients without renal impairment. Similarly, CLr was decreased to 3 and 1 L/hr in moderate and severe renal impairment patients, respectively, compared with 5 to 7 L/hr in non-renal impairment patients. Dosage reduction in patients with renal dysfunction not on dialysis is necessary.
Gabapentin is effectively removed from plasma by hemodialysis. The mean percentage of gabapentin recovered following hemodialysis in patients with end-stage renal disease was 29% (expressed as a proportion of the gabapentin released from HORIZANT). For patients with PHN on hemodialysis, dosage reduction is required [see DOSAGE AND ADMINISTRATION]. For patients with RLS on hemodialysis, treatment with HORIZANT is not recommended [see DOSAGE AND ADMINISTRATION].
Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes. Gabapentin enacarbil is neither a substrate or an inhibitor of P-glycoprotein in vitro.
Pharmacokinetic drug-drug interaction studies were conducted to examine the potential for an interaction of gabapentin enacarbil with cimetidine and naproxen. No significant pharmacokinetic interactions were observed. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of organic cation transporter type 2 (OCT2) and monocarboxylate transporter type 1 (MCT-1).
Ethanol: An in vitro dissolution study was conducted to evaluate the impact of ethanol (5, 10, 20, and 40%), on the extended-release characteristics of HORIZANT. The in vitro study showed that about 63% of the total gabapentin enacarbil dose was released at 1 hour at the highest alcohol level (40%), and about 43% of total drug was released at 1 hour with 5% alcohol. Ethanol causes a more rapid release of gabapentin enacarbil from the extended-release tablets that may increase the risk for adverse events associated with HORIZANT. Consumption of alcohol is not recommended when taking HORIZANT.
Cimetidine: Gabapentin released from HORIZANT is eliminated by renal clearance via OCT2. Cimetidine is a known substrate for this same elimination pathway. Coadministration of 1,200 mg of HORIZANT once daily with cimetidine 400 mg 4 times daily showed no effect on cimetidine exposure. There was an increase in AUC of gabapentin (24%) and a decrease in renal clearance of gabapentin (20%); these effects are not expected to be clinically relevant. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of OCT2.
Naproxen: The pathway for absorption of gabapentin enacarbil includes active transport via a proton-linked MCT-1. Coadministration of 1,200 mg of HORIZANT once daily with naproxen 500 mg twice daily, a known substrate of MCT-1, showed no effect on naproxen exposure or steady-state gabapentin Cmax and AUC. No clinically relevant pharmacokinetic interactions are expected between HORIZANT and other substrates of MCT-1.
Morphine: Administration of a single 600-mg dose of HORIZANT 2 hours after a single 60-mg dose of extended-release morphine sulfate in 18 subjects was associated with increased somnolence/sedation, dizziness, and nausea for the combination compared to HORIZANT or morphine alone as measured by the visual analog scale. No changes in Cmax and AUC of gabapentin, morphine or its active metabolite morphine-6-glucuronide were observed.
At a dose of 6,000 mg, gabapentin enacarbil does not prolong QTc to a clinically relevant extent.
Restless Legs Syndrome (RLS) 12-Week Pivotal Studies
The effectiveness of HORIZANT in the treatment of moderate-to-severe primary RLS was demonstrated in two 12-week clinical studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations, symptoms begin or worsen during periods of rest or inactivity such as lying or sitting, symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues, and symptoms are worse or occur only in the evening or night. Patients were required to have a total score of ≥ 15 on the International Restless Legs Syndrome (IRLS) Rating Scale at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, iron deficiency anemia) were excluded. In study 1, patients were randomized to receive 1,200 mg of HORIZANT (N = 112) or placebo (N = 108) taken once daily at about 5 PM with food. In study 2, patients were randomized to receive 600 mg of HORIZANT (N = 114), 1,200 mg of HORIZANT (N = 111), or placebo (N = 96) taken once daily at about 5 PM with food.
Efficacy was evaluated using the IRLS Rating Scale and Clinical Global Impression of Improvement (CGI-I) scores. The IRLS Rating Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence/sedation, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I Scale allows the investigator to rate the patient's overall change in RLS symptoms since baseline, whether or not in the opinion of the investigator the change is related to study drug treatment. The change from baseline in the IRLS Rating Scale at Week 12 and the proportion of responders on the CGI-I Scale defined as a rating of “much improved” or “very much improved” at Week 12 were co-primary outcomes in these studies.
In these 2 studies, the mean age of patients studied was 50 years (range: 18 to 81 years); 59% of the patients were female. The racial distribution for these studies was as follows: Caucasian, 95%; black, 2%; and other, 3%.
Statistically significant differences (P < 0.05) between the treatment groups receiving 600 and 1,200 mg of HORIZANT and the group receiving placebo were observed at Week 12 for both the mean change from baseline in the IRLS Scale total score and the proportion of responders (“much improved” or “very much improved”) on the CGI-I Scale as described in Table 6.
Table 6: Mean Change in IRLS Scale Total Score and
Proportion of Responders on CGI-I Scale at Week 12
|Week 12||Study 1||Study 2|
|HORIZANT 1,200 mg
(N = 112)
(N = 108)
|HORIZANT 600 mg
(N = 114)
|HORIZANT 1,200 mg
(N = 111)
(N = 96)
|Mean Change in IRLS Score||-13.2||-8.8||-13.8||-13.0||-9.8|
|Proportion of Respondersa on CGI-I||76%||39%||73%||77%||45%|
|a CGI-I Responders = “much improved” and “very much improved.”|
Figure 1 presents the improvement in mean IRLS Rating Scale total score in patients treated with placebo or 600 or 1,200 mg of HORIZANT over the 12 weeks of treatment in study 2.
Figure 1: Study 2, Mean (±SD) IRLS
Rating Scale Total Score Over 12 Weeks (Observed Case Data, Modified
Postherpetic Neuralgia (PHN) 12-Week Study
The efficacy of HORIZANT for the management of postherpetic neuralgia was established in a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12- week study evaluating the efficacy, safety, and dose response of 3 maintenance doses of HORIZANT (1,200, 2,400, and 3,600 mg/day, with 107, 82, and 87 patients in each dosing group, respectively). Patients greater than 18 years of age with a documented medical diagnosis of PHN of at least three months duration were enrolled. To ensure that patients had significant pain, randomized patients were required to have a minimum baseline 24-hour average Pain Intensity Numerical Rating Scale (PI-NRS) intensity score of at least 4.0 on the 11-point numerical PI-NRS, ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”).
In this study, a total of 276 patients received HORIZANT while 95 patients received placebo. Following a 1-week baseline period during which patients were screened for eligibility, patients began a 1-week up-titration period followed by a 12-week maintenance treatment period, and then a 1-week down-titration period.
Treatment with HORIZANT statistically significantly improved the mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline at all doses tested. A benefit over placebo was observed for all 3 doses of HORIZANT as early as Week 1 and maintained to the end of treatment. Additional benefit of using doses of greater than 1,200 mg a day was not demonstrated.
For various degrees of improvement in pain from baseline to end of maintenance treatment, Figure 2 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 2: Percent of Patients Achieving Various Levels
of Improvement in Pain Intensity
Effects On Driving
Driving performance was assessed in a three way crossover study in healthy volunteers (mean age 36 years). Subjects were dosed at approximately 5 pm with HORIZANT 600 mg (for five days), diphenhydramine 50 mg (1 dose), and placebo (for five days). After the last dose, driving was evaluated on a computer-based simulation for 1 hour in the evening approximately 2 to 4 hours after dosing (7 to 9 pm), in the morning after dosing (7 to 9 am), and at midday the day after dosing (11 am to 1 pm). The primary endpoint of the study was lane position variability. There was no difference in change from baseline in lane position variability for HORIZANT compared to placebo at any of the simulated driving timepoints. Secondary measures included speed variability and the occurrence of simulated crashes. Subjects in this study experienced simulated crashes as described in Table 7. At the times that simulated crashes occurred, there was an increase in average speed variability in the HORIZANT and diphenhydramine treated groups that was most notable in patients who experienced simulated crashes, but no increases in lane position variability. Later time points post-dosing or the effects of driving after more than five days of dosing with HORIZANT were not evaluated.
Table 7: Simulated Crashes at Evaluated Timepoints
|Simulated Driving Timepoint and Hours Post Dose||Baseline
N = 36 n (%)
N = 36 n (%)
|HORIZANT 600 mg
N = 35 n (%)
|Diphenhydramine 50 mg
N = 36 n (%)
|Evening (7 to 9 pm) 2 to 4 hours post dose||0 (0)||0 (0)||0 (0)||3 (9)|
|Morning (7 to 9 am) 14 to 16 hours post dose||2 (6)||1 (3)||1 (3)||0 (0)|
|Midday (11 am to 1 pm) 18 to 20 hours post dose||1 (3)||0 (0)||3 (9)||3 (8)|
The results of a separate 2-week driving simulation study in patients (mean age 47 years) with moderate-to-severe primary RLS showed that once daily doses of 1,200 mg and 1,800 mg of HORIZANT significantly impaired simulated driving performance based on lane position variability. An increased number of simulated crashes were reported in patients tested near Tmax after receiving 1,200 mg or 1,800 mg of HORIZANT compared to patients treated with diphenhydramine 50 mg. In addition, patients receiving 1,200 mg of HORIZANT experienced an increased number of simulated crashes at 14 to 16 hours after dosing compared with placebo, diphenhydramine, and 1,800 mg of HORIZANT.
The design limitations of these two studies do not permit inference regarding dose response relationship or the duration of the effect HORIZANT has on driving in patients with RLS.
The results of a separate driving simulation study comparing untreated RLS patients and healthy subjects showed no difference in lane position variability but an increase in speed variability associated with a greater number of simulated crashes in RLS patients relative to healthy subjects, which may indicate impaired driving in RLS patients in the absence of medication.
Last reviewed on RxList: 4/25/2016
This monograph has been modified to include the generic and brand name in many instances.
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