ensive 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.
Elimination: 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.
Special Populations: 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 (8.5)].
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 (2.3)]. For patients with RLS on hemodialysis, treatment with HORIZANT is not recommended [see Dosage and Administration (2.3)].
Drug Interactions: Neither gabapentin enacarbil nor gabapentin are substrates, inhibitors, or inducers of the major cytochrome P450 enzymes. Gabapen |
