Pharmacokinetic Effects of Simultaneous Administration of Single-Dose Gabapentin 500 mg and Zolpidem Tartrate 10 mg in Healthy Volunteers: A Randomized, Open-Label, Crossover Trial

Abstract

ObjectiveGabapentin is being investigated as a potential treatment for occasional disturbed sleep. This study assessed the pharmacokinetics and tolerability of gabapentin 500 mg and the commonly prescribed sedative/hypnotic zolpidem tartrate 10 mg, administered separately and in combination.MethodsForty healthy participants (19 male, 21 female) were randomized into this three-period crossover study [mean (range) age 34.1 (18–45) years, weight 68.3 (51.4–92.7) kg; 60 % white]. Participants were dosed with gabapentin alone (n = 39), zolpidem tartrate alone (n = 38), and the combination (gabapentin + zolpidem) (n = 38) over three treatment periods, which were separated by ≥7 days. Blood samples were collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 36 h post-dose. Plasma concentrations of each drug were assayed using validated methods. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard non-compartmental methods.ResultsFor gabapentin + zolpidem combination versus gabapentin alone, mean pharmacokinetic parameters were peak plasma concentration (Cmax) 4.61 versus 4.72 µg/mL, time to Cmax (tmax) 4.63 versus 3.64 h and the area under plasma concentration–time curve extrapolated to infinity (AUC0–∞) 53.4 versus 51.0 µg h/mL. For the combination versus zolpidem alone, mean pharmacokinetic parameters were Cmax 154 versus 138 ng/mL, tmax 1.45 versus 1.84 h and AUC0–∞ 912 versus 854 ng h/mL. The 90 % confidence intervals for Cmax (rate of absorption) and AUC0–∞ (extent of absorption) comparing the combination versus single drug administration fell within the 80–125 % range accepted for bioequivalence. All treatments were well tolerated.ConclusionThe pharmacokinetics of gabapentin 500 mg and zolpidem tartrate 10 mg are unaffected when both drugs are taken simultaneously, compared with each drug taken alone.

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

“…Therefore, renal function (represented by eGFR) is the major covariate described up to date to explain the variability on GAB pharmacokinetics in both healthy individuals and patients receiving GAB. [18][19][20] Although OCTN1 is also expressed in the intestinal epithelium, no effect of SLC22A4 c.1507C>T polymorphism in the absorption process was observed in this study or reported in the literature. 21 The main limitation of this study is that non-linear absorption of GAB was not taken into account during PopPK modelling, due to the lack of bioavailability data.…”

“…In this study, only eGFR was considered to predict clearance. Therefore, renal function (represented by eGFR) is the major covariate described up to date to explain the variability on GAB pharmacokinetics in both healthy individuals and patients receiving GAB . Although OCTN1 is also expressed in the intestinal epithelium, no effect of SLC22A4 c.1507C>T polymorphism in the absorption process was observed in this study or reported in the literature …”

“…GAB does not bind to plasma proteins, is not metabolised and is eliminated unchanged in urine . Renal function showed a positive correlation with GAB renal clearance, since GAB is mainly eliminated by glomerular filtration . However, studies suggested the activity of the organic cation transporters OCT2 and OCTN1 in the renal excretion of GAB …”

“…[15][16][17] Renal function showed a positive correlation with GAB renal clearance, since GAB is mainly eliminated by glomerular filtration. [18][19][20] However, studies suggested the activity of the organic cation transporters OCT2 and OCTN1 in the renal excretion of GAB. 21,22 OCT2 and OCTN1 are coded by SLC22A2 and SLC22A4 genes, respectively.…”

Influência do inibidor do transportador de cátions orgânicos 2 (OCT2) cimetidina e do diabetes experimental na disposição cinética da gabapentina em ratos

“…A absorção oral da GAB é variável e dados sugerem grande variabilidade interindividual associada a este processo (GIDAL et al, 2000). O tempo necessário para alcançar a concentração máxima (Tmáx) da GAB em dose única, em humanos, varia de 2-3h após a administração oral (WALKER; PATSALOS, 1995;GIDAL et al, 2000;BOCKBRADER et al, 2010;KRASOWSKI, 2010;TJANDRAWINATA et al, 2014;GALITZ, JAYAWARDENA, S.;FUREY, 2015), e em doses múltiplas varia de 2 à 17h, com mediana de 8h (GORDI et al, 2008). A biodisponibilidade oral (F) da GAB varia de 29-60% (ELWES; BINNIE, 1996;GIDAL et al, 1998;GIDAL et al, 2000;YAGI et al, 2012 (VARMA et al, 2015;EL-KATTAN et al, 2016;EL-KATTAN e VARMA, 2018).…”