12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. 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 is unknown.
All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans.
Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and Cmax).
Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
The effect of age was studied in subjects 20–80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)].
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.
Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied.
A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given three times a day. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady-state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range.
These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day [see Dosage and Administration (2.2)].
Adult Patients with Renal Impairment
Subjects (N=60) with renal impairment (mean creatinine clearance ranging from 13–114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. Pediatric patients with renal insufficiency have not been studied.
In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
- In Vitro Studies
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day).
- In Vivo Studies
The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.
- In a single (400 mg) and multiple dose (400 mg three times a day) study of NEURONTIN in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics.
- Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg three times a day; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration.
- Valproic Acid
- The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg three times a day; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid.
- Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg three times a day; N=12) are identical whether the drugs are administered alone or together.
- Coadministration (N=18) of naproxen sodium capsules (250 mg) with NEURONTIN (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known.
- Coadministration of NEURONTIN (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg NEURONTIN and 21% to 22% lower, respectively, after administration of 500 mg NEURONTIN. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known.
- A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg NEURONTIN capsule (N=12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Morphine pharmacokinetic parameter values were not affected by administration of NEURONTIN 2 hours after morphine. The magnitude of interaction at other doses is not known.
- In the presence of cimetidine at 300 mg four times a day (N=12), the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated.
- Oral Contraceptive
- Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg three times a day; N=13). The Cmax of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance.
- Antacid (Maalox®) (aluminum hydroxide, magnesium hydroxide)
- Antacid (Maalox®) containing magnesium and aluminum hydroxides reduced the mean bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 10% when gabapentin was administered 2 hours after Maalox.