Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: A randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects

Gordi, Toufigh; Hou, Eddie; Kasichayanula, Sreeneeranj; Berner, Bret

doi:10.1016/j.clinthera.2008.05.008

Cited by 59 publications

(40 citation statements)

References 13 publications

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“…Pharmacokinetic studies of gabapentin ER at steady state indicate that although the total amount of drug absorbed over 24 hours is similar for once-daily and twice-daily dosing, the minimum gabapentin plasma concentration over a 24-hour period is lower with once-daily than twice-daily dosing. 22 Additionally, with twice-daily dosing, the minimum gabapentin concentration was similar to gabapentin immediate release tablets, 600 mg administered 3 times/d, whereas the once daily dosing of gabapentin ER was somewhat less than gabapentin immediate release tablets. Thus, with oncedaily dosing, it is possible that plasma levels may fall below the therapeutic range before the end of the 24-hour dosing period.…”

Section: Discussionmentioning

confidence: 97%

“…16,21 This slow release of drug may help to overcome the saturable transport mechanism of gabapentin and offers the potential for increased bioavailability of the drug while decreasing the dose frequency. 22 The objective of this study was to determine whether this extended-release formulation was effective for the treatment of PHN with fewer daily doses (1 or 2/d) than the 3 or more doses per day typically required for optimal efficacy with gabapentin, an immediate-release formulation. It was hypothesized that giving the once-daily dose in the evening and the twice-daily dose asymmetrically (600 mg AM and 1200 mg PM) could result in improved quality and duration of sleep, while maintaining pain relief during the day.…”

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confidence: 99%

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Efficacy and Tolerability of Gastric-retentive Gabapentin for the Treatment of Postherpetic Neuralgia

Irving

Jensen

Cramer

et al. 2009

The Clinical Journal of Pain

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Efficacy and Tolerability of Gastric-retentive Gabapentin for the Treatment of Postherpetic Neuralgia

Irving

Jensen

Cramer

et al. 2009

The Clinical Journal of Pain

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“…In addition, a recent study compared 600 mg of Neurontin™ tid to an 1,800-mg gastric-retentive extended release formulation (50). The published distributions of intestinal OCTN1 (25) and intestinal LAT2 (29) were used for the GastroPlus simulations of gabapentin.…”

Section: Physiologically Based Pharmacokineticsmentioning

confidence: 99%

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

Bolger

Lukáčová

Woltosz

2009

AAPS J

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Abstract. The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus™ was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro K m value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.

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“…Significant efforts have been made using a range of materials, including bioadhesives 4 and swellable polymers 6 . But so far, systems are able to provide extended release times only on the order of hours.…”

Section: Potential Challengesmentioning

confidence: 99%

Perspective: Special delivery for the gut

Traverso

Langer

2015

Nature

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succinct analysis by former US surgeon general C. Everett Koop points the way towards the huge contribution that biomaterials technology can make to health care.The failure of patients to follow instructions for taking medication is a major barrier to effective clinical care. In developed nations, adherence to long-term therapies is only 50%, and it is much lower in developing countries and in people who take multiple drugs with complex dose regimens 1 . Medication non-adherence is estimated to cost more than US$100 billion in avoidable hospitalizations every year in the United States. Technologies that would enable extended drug release -lasting for up to several months -through the gastrointestinal (GI) tract could therefore radically improve delivery of medical therapies. This may be especially useful for patients in areas afflicted by war, regions with poor access to health care, patients suffering from psychiatric illness or dementia, and paediatric populations.There is good reason to suppose that the gut could host long-acting medication -known as depot formulations -for weeks or even months without significant adverse effects. We know this, for example, from observation of patients with bezoars -indigestible masses trapped in the GI tract that typically pose no problem until they grow quite large 2 . Patients also are generally able to tolerate intra-gastric balloons for several months 3 in their quest to lose weight. POTENTIAL CHALLENGESBut translating this possibility into a reality poses a big challenge. To begin with, the gut's typical healthy transit time (from mouth to anus) is about 30 hours. This transit would have to be extended significantly for a drug to achieve weekly or monthly dosing. Furthermore, the GI environment has tremendous variability: pH in different sections ranges from 1 (extremely acidic) to 7 (neutral). Natural variability in the timing and content of meals results in frequent changes in lipid abundance. Then there are the high bacterial loads, 100% humidity, 37 °C temperature and a huge variety of proteases, lipases and other enzymes that work against biomaterial integrity and long-term drug stability. Thus it is imperative to prolong this transit time, which in turn requires developing materials that can withstand extreme conditions while delivering the drug continuously and without compromising safety.There are two basic engineering approaches to extend transit time. One is to slow a drug's passage through the GI system by using devices that increase friction with the gut's mucosal walls 4 . The other is to prolong retention by loading drugs into devices that are larger than the points in the gut that limit passage of materials beyond a certain size: the pyloric sphincter at the exit of the stomach and the anus 5 . Also crucial to the successful development of such technologies are ways to ensure that drugs survive the harsh GI environment.Significant efforts have been made using a range of materials, including bioadhesives 4 and swellable polymers 6 . But so far, systems are...

show abstract

Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: A randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects

Cited by 59 publications

References 13 publications

Efficacy and Tolerability of Gastric-retentive Gabapentin for the Treatment of Postherpetic Neuralgia

Efficacy and Tolerability of Gastric-retentive Gabapentin for the Treatment of Postherpetic Neuralgia

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

Perspective: Special delivery for the gut

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