Pharmacokinetics Of Gabapentin Research Articles

Pharmacokinetic report: Pharmacokinetics of a single oral dose of gabapentin in goats (Capra hircus).

Gabapentin is used in goats to treat chronic pain associated with lameness. However, pharmacokinetic data and clinical effectiveness trials are lacking. The objective of the study was to describe the pharmacokinetics of gabapentin in goats following a single oral dose. Six Spanish-crossbred goats were enrolled. Each goat was administered gabapentin at a target dose of 15 mg/kg per os. Serial blood samples were collected out to 60 h post-gabapentin administration for plasma gabapentin concentration determination. Plasma samples were analyzed for gabapentin concentration using ultra-high-pressure liquid chromatography coupled with mass spectroscopy. Individual animal pharmacokinetic outcomes were determined using non-compartmental analysis. Gabapentin was detectable in the plasma of all goats at 60 h post-administration. The mean (±SD) Cmax was 2.01 ± 0.62 μg/mL which occurred at 8.47 ± 1.9 h. The mean terminal half-life (T1/2) and mean resident time were determined to be 8.52 ± 1.8 and 18.7 ± 4.0 h, respectively. This study indicates gabapentin is absorbed from the gastrointestinal tract of goats. Further research is needed to determine an optimal dose for clinical efficacy in goats.

Pharmacokinetics of gabapentin after single, oral administration in domestic rabbits (Oryctolagus cuniculus)

Gabapentin is used to treat seizures, neuropathic pain, and anxiety. Currently, dosage recommendations for rabbits are extrapolated from other species. The objective of this study was to determine the pharmacokinetics of gabapentin after single, oral administration in domestic rabbits. A randomized, crossover study was performed in male (n = 3) and female (n = 3) rabbits after administration of either 25 or 50 mg/kg gabapentin orally. Plasma concentrations of gabapentin were measured at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, and 48 hours post-administration via liquid chromatography. Mean maximum plasma concentrations were 17.70 and 16.83 µg/mL for the 25 and 50 mg/kg doses, respectively. Mean times to maximum plasma concentration were 1.75 and 1.5 hours, and mean terminal half-lives were 10.2 and 9.44 hours for the 25 and 50 mg/kg doses, respectively. No adverse effects observed at either dose. A single oral dose of gabapentin at 50 mg/kg did not result in higher plasma concentrations compared to the 25 mg/kg dose and no differences were observed between males and females for either dosing group (P > 0.9).

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control.

Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. GBP drug disposition was described by a 1-compartment model with lag-time, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22A4 genotypes. This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.

Plasma disposition of gabapentin after the intragastric administration of escalating doses to adult horses.

BackgroundIn humans, gabapentin an analgesic, undergoes non‐proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses.Hypothesis and ObjectivesGabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses.AnimalsNine clinically healthy adult Arabian and Quarter Horses.MethodsIn a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis.ResultsPlasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses.Conclusions and Clinical ImportanceGabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

The pharmacokinetics of gabapentin in cats.

BackgroundGabapentin is the most commonly prescribed medication for the treatment of chronic musculoskeletal pain in cats. Despite this common and chronic usage, clinically relevant pharmacokinetic data is lacking.ObjectivesTo evaluate the pharmacokinetics of clinically relevant dosing regimens of gabapentin in cats.AnimalsEight research‐purpose mixed‐breed cats.MethodsCats were enrolled in a serial order, non‐randomized pharmacokinetic study. Gabapentin was administered as an IV bolus (5 mg/kg), orally (10 mg/kg) as a single dose or twice daily for 2 weeks, or as a transdermal gel (10 mg/kg) in serial order. Serial blood samples were collected up to 48 hours. Plasma concentrations were determined using Ultra Performance Liquid Chromatography‐Mass Spectrometry. Compartmental analysis was used to generate gabapentin time‐concentration models.ResultsAfter IV administration CL (median (range)) and terminal half‐life were 160.67 mL/kg*hr (119.63‐199.11) and 3.78 hours (3.12‐4.47), respectively. The oral terminal half‐life was 3.63 hours (2.96‐4.77), and 3.72 hours (3.12‐4.51) for single and repeated dosing. TMAX and CMAX, as predicted by the model were 1.05 hours (0.74‐2.11), and 12.42 μg/mL (8.31‐18.35) after single oral dosing, and 0.77 hours (0.58‐1.64), and 14.78 μg/mL (9.70‐18.41) after repeated oral dosing. Bioavailability after a single oral dose was 94.77% (82.46‐122.83).ImportanceRepeated oral dosing of gabapentin did not alter the drug's pharmacokinetics, making dose adjustments unnecessary with long‐term treatment. As prepared, the transdermal route is an inappropriate choice for drug administration. These relevant data are important for future studies evaluating potential efficacy of the medication for treating chronic pain states in cats.

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1.

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860h-1, and the lag time was predicted at 0.311h. Oral bioavailability was estimated to be 68.8% at dose of 300mg, 62.7% at dose of 400mg, and 47.1% at dose of 800mg. The creatinine clearance significantly influenced on the oral clearance (P<0.005) and ABCB1 2677G>T/A genotypes significantly influenced on the absorption rate constant (P<0.05) of gabapentin. However, ABCB1 1236C>T and 3435C>T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G>T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients.

Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.

Pharmacokinetics of Compounded Intravenous and Oral Gabapentin in Hispaniolan Amazon Parrots ( Amazona ventralis ).

Neuropathic pain is a manifestation of chronic pain that arises with damage to the somatosensory system. Pharmacologic treatment recommendations for alleviation of neuropathic pain are often multimodal, and the few reports communicating treatment of suspected neuropathic pain in avian patients describe the use of gabapentin as part of the therapeutic regimen. To determine the pharmacokinetics of gabapentin in Hispaniolan Amazon parrots ( Amazona ventralis ), compounded gabapentin suspensions were administered at 30 mg/kg IV to 2 birds, 10 mg/kg PO to 3 birds, and 30 mg/kg PO to 3 birds. Blood samples were collected immediately before and at 9 different time points after drug administration. Plasma samples were analyzed for gabapentin concentration, and pharmacokinetic parameters were calculated with both a nonlinear mixed-effect approach and a noncompartmental analysis. The best compartmental, oral model was used to simulate the concentration-time profiles resulting from different dosing scenarios. Mild sedation was observed in both study birds after intravenous injection. Computer simulation of different dosing scenarios with the mean parameter estimates showed that 15 mg/kg every 8 hours would be a starting point for oral dosing in Hispaniolan Amazon parrots based on effective plasma concentrations reported for human patients; however, additional studies need to be performed to establish a therapeutic dose.

Clinical pharmacology and pharmacoepidemiology for medication safety in clinical settings

In this review, optimization of individualized analgesic therapy in cancer-pain patients (1), pharmacoepidemiological studies using a hospital database (DB) (2), and other clinical and practical research studies (3) were summarized. (1) The aim of the analgesic study was to evaluate individual factors in the effects of pain-relief, and ADR of analgesics from the viewpoints of clinical pharmacokinetics and pharmacodynamics. Oxycodone, fentanyl, and gabapentin were used. For the dose escalation and ADR of oxycodone, the plasma disposition of noroxycodone regulated by CYP3A5 polymorphisms and cancer cachexia were found to be individual factors. The ADR and clinical response of fentanyl were affected by polymorphisms of CYP3A5 and ABCB1. In the pharmacokinetics of gabapentin, concomitant magnesium oxide reduced the intestinal absorption of gabapentin. (2) The aim of the DB study was to demonstrate a pharmacoepidemiological advantage using a hospital DB of a million-scale for post-marketing safety management. We tried to detect fluoroquinolone (FQ)-induced tendon disorders, because its risk ratio in Japan has not been clarified. The risk of a tendon disorder in FQ-prescribed patients was 0.082% (95%CI: 0.049-0.137%), and significantly higher than that in cephalosporin-prescribed patients. The risk ratio in FQ-prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95%CI: 2.27-17.46). (3) Individual variation of plasma exposure of free linezolid and its ratio to minimum inhibitory concentration in critically ill patients, as well as three other studies, were described. In conclusion, our achievement in accurately assessing these would contribute to medication safety and the appropriate use of medicines in clinical settings.

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.

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 (C max) 4.61 versus 4.72 µg/mL, time to Cmax (t max) 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 C max 154 versus 138 ng/mL, t max 1.45 versus 1.84 h and AUC0–∞ 912 versus 854 ng h/mL. The 90 % confidence intervals for C max (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.

Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects

This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption. Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg. Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min(-1) , P = 0.031). No significant changes in AUC(0,tlast ) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin. These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast ) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.

Investigation on Gabapentin Residues in Eggs from Free-Range Hens Exposed to Saline Slags from Pharmaceutical Industry

A simple, sensitive and rapid liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed and validated to monitor the presence of gabapentin as environmental contaminant in albumen and yolk of eggs from grazing flocks exposed to open air stored saline wastes from pharmaceutical industry. The method involved a simple liquid extraction followed by a gradient elution with formic acid 0.2 % and acetonitrile in reverse phase. ESI ionization was performed in positive ion mode. The tandem mass spectrometer was operated in multiple reaction monitoring mode. The calibration curves were linear in the concentration range from 5 to 400 ng/g for the two matrices with correlation coefficients that exceeded 0.990. The limits of quantitation were 12.0 and 14.8 ng/g in albumen and yolk, respectively. Results are discussed in light of the pharmacokinetics of gabapentin in experimentally exposed hens, accounting for the top soil intake in such free grazing animals.

Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain

In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund's adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC(50)) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL=0.159lh(-1), V(2)=0.118l, V(3)=0.253l, Ka=0.26h(-1), Q=1.22lh(-1)). Drug potency (EC(50)) for the anti-allodynic effects was estimated to be 1400ngml(-1). Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9.%, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91%, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.

Steady-State Pharmacokinetics of Gabapentin after Administration of a Novel Gastroretentive Extended-Release Formulation in Postmenopausal Women with Vasomotor Symptoms

Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease. Gabapentin has also been demonstrated to be efficacious in the treatment of vasomotor symptoms in postmenopausal women when administered three times a day. A gastroretentive extended-release formulation of gabapentin (gabapentin-ER) has recently been demonstrated to be efficacious in the treatment of postmenopausal hot flashes. The objective of this paper is to report the steady-state pharmacokinetics and safety of gabapentin with different dosing regimens of gabapentin-ER in postmenopausal women with hot flashes. This was a multicentre, randomized, double-blind, dose-escalating, placebo-controlled, parallel group study in 124 postmenopausal women experiencing ≥7 moderate to severe hot flashes per day. The study consisted of two 5-week treatment periods, with each one preceded by a 1-week titration to the assigned dose. Groups A, B and C received gabapentin-ER 600 mg evening (pm), 600 mg morning (am)/600 mg pm and 1200 mg pm in the first period, and then 600 mg am/1200 mg pm, 600 mg am/1800 mg pm and 1200 mg am/1800 mg pm in the second period, respectively. The tablets were taken after a non-specified meal. Pharmacokinetic sampling was conducted over a 24-hour period at the end of each study period. Plasma samples were analysed by a validated liquid chromatography tandem mass spectrometry method. Non-compartmental pharmacokinetic analysis was performed on the concentration-time data to determine area under the plasma concentration versus time curve from time zero to 24 hours (AUC(24)). Maximum (C(max)), minimum (C(min)) and average (C(avg)) drug concentration and time to reach C(max) (t(max)) were determined by inspection of the data. Tolerability was evaluated by physical examination, clinical laboratory measurements and adverse events monitoring. Gabapentin exposure at steady state, as measured by AUC(24), increased with doses from 600 mg/day to 3000 mg/day, although there was a slight decrease in gabapentin's relative bioavailability with increasing dose compared with the 600 mg dose. The relative bioavailability compared with the 600 mg dose was 86-88% for the 1200 mg/day doses, 75% for the 1800 mg/day dose, 84% for the 2400 mg/day dose, and 73% for the 3000 mg/day dose. C(max) generally increased with increasing dose as did C(min) and C(avg) for the various treatments in a manner that was consistent with the dosing regimen. The values of t(max) were not different between the various doses, with the median t(max) values relative to the most recent dose ranging from 6 to 8 hours for all dose levels. Gabapentin-ER was generally well tolerated at all doses studied. The most common AEs were headache, dizziness and somnolence, with most being mild in intensity. Seven patients withdrew from the study due to AEs. The pharmacokinetic profile of gabapentin-ER may allow for once- or twice-daily dosing while maintaining bioavailability and thus efficacy. Gabapentin-ER was well tolerated. Registered as ClinicalTrials.gov Identifier: NCT00511953.

Steady-State Pharmacokinetics of Gabapentin after Administration of a Novel Gastroretentive Extended-Release Formulation in Postmenopausal Women with Vasomotor Symptoms

Steady-State Pharmacokinetics of Gabapentin after Administration of a Novel Gastroretentive Extended-Release Formulation in Postmenopausal Women with Vasomotor Symptoms

Treatment of gabapentin-induced myoclonus with continuous renal replacement therapy

A 56-year-old man with diabetes, hypertension, and chronic kidney disease presented to the emergency room with a complaint of pain in his right foot. He was found to have tremors. Gabapentin toxicity was suspected and the patient was found to have high gabapentin level (6.3 mcg/ml). Patient was commenced on continuous venovenous hemodiafiltration (CVVHD) and the pharmacokinetics of gabapentin was studied. The patient improved symptomatically and his tremors subsided. In this case report, we describe the successful management of gabapentin toxicity with continuous renal replacement therapy and calculate the clearance of gabapentin which will enable future treatment of gabapentin toxicity by CVVHD.

Clinical Pharmacokinetics of Gabapentin After Administration of Gabapentin Enacarbil Extended-Release Tablets in Patients With Varying Degrees of Renal Function Using Data From an Open-Label, Single-Dose Pharmacokinetic Study

BackgroundGabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance. Gabapentin produced from hydrolysis of gabapentin enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of gabapentin derived from gabapentin enacarbil would also be affected by renal function. ObjectiveThe objective of this study was to describe a population pharmacokinetic analysis of gabapentin enacarbil in patients with varying degrees of renal function, using data from an open-label study of gabapentin enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment. MethodsMen and women >18 years of age with a body mass index ≤34 kg/m2 and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg gabapentin enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I–III studies in subjects with normal renal function to evaluate the relationship between gabapentin oral clearance (CL/F) and CrCL. ResultsFifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30–59 mL/min), 7 patients had severe renal impairment (CrCL <30 mL/min), and 7 patients had end-stage renal disease (CrCL <15 mL/min). Ten patients were white, 4 were African American, and 1 was American Indian or Alaskan Native. Their mean (range) age was 55 (28–76) years, weight was 85.6 (62–134) kg, and body mass index was 28.3 (22–34) kg/m2. Mean maximum plasma gabapentin concentration was 5.77 μg/mL in patients with moderate and severe renal impairment, and 5.59 μg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, gabapentin CL/F after administration of gabapentin enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae. ConclusionsThe data suggest that dosage adjustment for gabapentin enacarbil is necessary in patients with impaired renal function. Gabapentin enacarbil, 600 mg, seemed to be well tolerated in this small selected population.

Efficacy of Gabapentin Enacarbil vs Placebo in Patients with Postherpetic Neuralgia and a Pharmacokinetic Comparison with Oral Gabapentin

The efficacy of gabapentin in some patients with postherpetic neuralgia (PHN) may be limited by suboptimal drug exposure from unpredictable and saturable absorption. Gabapentin enacarbil (GEn) was designed for absorption by high-capacity transporters expressed throughout the intestine and undergoes rapid postabsorption hydrolysis to gabapentin. GEn extended-release tablets provide sustained, dose-proportional gabapentin exposure. This study assessed the efficacy of GEn vs placebo and compared the pharmacokinetics of gabapentin after oral dosing of GEn or gabapentin in patients with PHN. In this double-blind, randomized study, 115 patients with PHN completed a 7-day baseline period and 11-day gabapentin run-in period. Eligible patients were randomized and 101 received double-blind GEn 1,200 mg (624 mg-equivalents gabapentin) (n = 47) or placebo (n = 54), twice daily for 14 days. We evaluated patient-reported pain, sleep, mood, global improvement, and adverse events, plus gabapentin pharmacokinetics. The improvement in mean weekly pain scores from baseline to the end of treatment (primary endpoint) was significantly greater for GEn (-2.1) vs placebo (-1.2), P = 0.0321. Significant improvements from GEn vs placebo were also seen in sleep, mood, and patient global assessment (P < 0.05). With a 31% lower daily dose of gabapentin equivalents, GEn tablets provided a significant increase in average steady state gabapentin concentrations vs gabapentin capsules in the same patients (n = 42; P = 0.0050). GEn was effective in providing PHN pain relief, improved gabapentin exposure compared with gabapentin capsules, and was generally safe and well tolerated in patients with PHN.

Pharmacokinetics of Gabapentin in a Novel Gastric-Retentive Extended-Release Formulation: Comparison With an Immediate-Release Formulation and Effect of Dose Escalation and Food

The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (t(max)) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed t(max) and enhanced C(max) and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form.

Pharmacokinetics of gabapentin in cats

To determine the pharmacokinetics of gabapentin in cats after IV and oral administration. 6 healthy female adult domestic shorthair cats. Gabapentin was administered IV (4 mg/kg) or orally (10 mg/kg) in a crossover randomized design. Blood samples were obtained immediately before gabapentin administration and at various times up to 960 minutes after IV administration or up to 1,440 minutes after oral administration. Blood samples were immediately transferred to tubes that contained EDTA and were centrifuged at 4 degrees C. Plasma was harvested and stored at -20 degrees C until analysis. Plasma concentrations of gabapentin were determined by use of liquid chromatography-mass spectrometry. Gabapentin concentration-time data were fit to compartment models. A 3-compartment model with elimination from the central compartment best described the disposition of gabapentin administered IV to cats, but a 1-compartment model best described the disposition of gabapentin administered orally to cats. After IV administration, the mean +/- SEM apparent volume of the central compartment, apparent volume of distribution at steady state, and clearance and the harmonic mean +/- jackknife pseudo-SD for terminal half-life were 90.4 +/- 11.3 mL/kg, 650 +/- 14 mL/kg, 3 +/- 0.2 mL/min/kg, and 170 +/- 21 minutes, respectively. Mean +/- SD systemic availability and harmonic mean +/- jackknife pseudo-SD terminal half-life after oral administration were 88.7 +/- 11.1% and 177 +/- 25 minutes, respectively. The disposition of gabapentin in cats was characterized by a small volume of distribution and a low clearance.