The pharmacokinetics of gabapentin TID have been described in detail elsewhere [Vollmer et al. 1986
] and the distribution, metabolism, and excretion of once-daily gastroretentive gabapentin are similar to gabapentin TID. Gabapentin is not appreciably bound to plasma proteins or metabolized and is almost completely eliminated unchanged by renal excretion.
The absorption of once-daily gabapentin is, however, unique because the application of gastroretentive technology has provided a means to address the limitations of gabapentin TID. This gastroretentive technology has also been employed in approved formulations of metformin (Glumetza; Santarus Inc., San Diego, CA, USA). When administered with a meal, the once-daily gabapentin tablet swells upon contact with gastric juices to a size that promotes gastric retention for several hours when taken with a meal [Hou et al. 2003
; Waterman, 2007
]. This gastric retention results in the gradual release of gabapentin to the proximal small intestine at a relatively constant rate over 8–10 h whereas gabapentin TID is completely emptied from the stomach in 30 min. The gradual release of gabapentin from the once-daily gabapentin tablet retained in the stomach extends the time of exposure to the site of absorption in the proximal small intestine and reduces the chance of saturating intestinal uptake. After the drug has been released, the tablet matrix dissolves in about 15 h post dosing [Hou et al. 2003
; Berner and Cowles, 2006
The pharmacokinetics of gabapentin TID have been compared with the once-daily gastroretentive formulation in several crossover pharmacokinetic studies in healthy volunteers. In the first study, the pharmacokinetics of single 600 mg doses of gabapentin TID and once-daily gastroretentive gabapentin were compared. Following administration of 600 mg of gabapentin TID, peak plasma concentrations occurred at approximately 4 h and then rapidly declined. Following administration of 600 mg of once-daily gastroretentive gabapentin, the time to maximum concentration (Tmax
) was prolonged (to 6 h), the area under the concentration–time curve (AUC) was similar to gabapentin TID, the peak levels were lower, and the decline in plasma gabapentin levels was more gradual () [Chen et al. 2011
]. The terminal elimination half life, urinary recovery, and renal clearance were similar for once-daily gastroretentive gabapentin and gabapentin TID.
Figure 1. Mean (standard error) plasma concentrations of gabapentin following a single 600 mg dose of gabapentin TID (n = 15) and once-daily gastroretentive gabapentin (n = 16) in healthy volunteers under fed conditions. Adapted from Chen et al. , with permission. (more ...)
Steady-state pharmacokinetics of once-daily gastroretentive gabapentin were compared with gabapentin TID during daily dosing for up to 8 days [Gordi et al. 2008
] in a 24-subject three-way crossover study. Subjects received either 1800 mg/day of gastroretentive gabapentin dosed either once daily (QD) (8:00 p.m.) or as an asymmetric divided dose (DD) (600 mg at 8:00 a.m. and 1200 mg at 8:00 p.m.) or gabapentin TID given three times daily (600 mg at 8:00 a.m., 2:00 p.m. and 8:00 p.m.). Plasma concentrations of gabapentin reached a steady state after day 3 of dosing, and the systemic exposure was comparable for all three treatments. When gastroretentive gabapentin was administered QD, the Cmax
was slightly higher and the minimum concentration (Cmin
) was lower compared with gabapentin TID. When gastroretentive gabapentin was given as an asymmetric DD, the Cmax
was slightly lower and the Cmin
slightly higher than with gabapentin TID ().
Single-dose and steady-state pharmacokinetic parameters of once-daily gastroretentive gabapentin.
The effect of food on the pharmacokinetics of gastroretentive gabapentin QD was examined under fasting, low-fat, and high-fat conditions [Chen et al. 2011
]. The terminal half life of gabapentin was comparable between fasted and fed subjects, but compared with fasted subjects, the Cmax
, AUC, and Tmax
values were higher in fed subjects and were highest in those fed a high-fat meal. These observations suggest that gabapentin QD tablets are retained longer when taken with food and that the fat content of the food may play an important role in that effect.