Plasma Concentrations Of Gabapentin Research Articles

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).

Pharmacokinetic Profiles of Gabapentin after Oral and Subcutaneous Administration in Black-tailed Prairie Dogs (Cynomys ludovicianus).

In veterinary and human medicine, gabapentin (a chemical analog of γ-aminobutyric acid) is commonly prescribed to treat postoperative and chronic neuropathic pain. This study explored the pharmacokinetics of oral and subcutaneous administration of gabapentin at high (80 mg/kg) and low (30 mg/kg) doses as a potential analgesic in black-tailed prairie dogs (Cynomys ludovicianus; n = 24). The doses (30 and 80 mg/kg) and half maximal effective concentration (1.4 to 16.7 ng/mL) for this study were extrapolated from pharmacokinetic efficacy studies in rats, rabbits, and cats. Gabapentin in plasma was measured by using an immunoassay, and data were evaluated using noncompartmental analysis. The peak plasma concentrations (mean ±1 SD) were 42.6 ±14.8 and 115.5 ±15.2 ng/mL, respectively, after 30 and 80 mg/kg SC and 14.5 ±3.5 and 20.7 ±6.1 ng/mL after the low and high oral dosages, respectively. All peak plasma concentrations of gabapentin occurred within 5 h of administration. Disappearance half-lives for the low and high oral doses were 7.4 ± 6.0 h and 5.0 ± 0.8 h, respectively. The results of this study demonstrate that oral administration of gabapentin at low (30 mg/kg) doses likely would achieve and maintain plasma concentrations at half maximum effective concentration for 12 h, making it a viable option for an every 12-h treatment.

O-20 Predictions of systemic drug exposure to gabapentin and tramadol following administration to children

Background Gabapentin and tramadol are drugs com-monly used in various treatment of pain in adults. Gab-apentin has been successfully given for neuropathic pain and has been used off-label to treat children with the same condition. Tramadol has been licensed for the use in children older than 1 month in some European coun-tries, but its use has been limited to children>12 years. The management of chronic pain in paediatric patients is burdened by the insufficiency of clinical information, therefore, in order to investigate appropriate dosing for this population, pharmacokinetic (PK) modelling and simulation of virtual patient groups is a most useful ap-proach. In this study we report the analyses used to characterise the population PK and corresponding hier-archical models that are required to provide an adequate description of the time course and variability of drug con-centrations in plasma. Methods Non-linear, mixed-effect modelling was used to simulate the plasma concentrations of gabapentin and tramadol in subjects between the ages of 3 months and 18 years, under the assumption of comparable ex-posure-response relationships in adult and paediatric patients. Previously published PK models in paediatric pa-tients by Ouellet et al1 and Garrido et al2 were chosen and adapted for gabapentin and tramadol, respectively. Dosing regimens for both drugs were evaluated in a co-hort of virtual patients, based upon off-label doses used empirically. The population for the simulations was con-structed using data from the NHANES database; individu-al body weight was the primary covariate factor affecting PK disposition. The exposure (AUC) and Cmax parameters were derived from the simulated plasma concentrations, to compare with efficacious adult levels. Both drugs are titrated to a maximum dose over a period of 3 weeks, giv-en three times daily. Results The desired exposure in children should be comparable to the median value obtained for area under the concentration vs. time curve at steady state. An adult AUC range of 25 mg/L*h to 75 mg/L*h corresponded to gabapentin dosing at 63 mg/kg/day and 45 mg/kg/day in patients weighing 5–15 kg and >15 kg, respectively (after a three week titration). Mean plasma concentrations of between 200–300 ng/mL were chosen as a target level for tramadol, and a titration scheme over a three week period up to a maximum of 8 mg/kg/day proceeded to achieve safe dosing. At the end of the titration phase, all weight groups showed drug exposure in the range shown to be safe and effective for the proposed regimens. Conclusion Clinical trial simulations showed how the proposed dosing regimens yielded suitable drug expo-sure in paediatric populations, suggesting a solution to the issue of under-or over-dosing in this subgroup, and informing appropriate dosage information. This informa-tion contributes to avoiding unnecessary adverse events or, conversely, ineffective treatment.

Gabapentin Improves Postcesarean Delivery Pain Management

Gabapentin is effective for preventing and treating acute and chronic postoperative pain; however, it has not been described for use in cesarean delivery. We hypothesized that preoperative gabapentin would reduce postcesarean delivery pain. Women undergoing scheduled cesarean delivery were randomized to receive preoperative gabapentin 600 mg, or placebo. Spinal anesthesia was achieved with 0.75% hyperbaric bupivacaine 12 mg, fentanyl 10 μg, and morphine 100 μg. Postoperative analgesia was initiated with intraoperative ketorolac and acetaminophen, and continued with postoperative diclofenac, acetaminophen, and morphine. Patients were assessed at 6, 12, 24, and 48 hours after spinal anesthesia for pain at rest and on movement using a visual analog scale (0 to 100 mm), satisfaction, opioid consumption, and side effects. Neonatal interventions, Apgar scores, umbilical artery blood gases, and breastfeeding difficulties were assessed. Chronic pain was assessed 3 months after delivery. Maternal and umbilical vein gabapentin plasma concentrations were measured in a subgroup of patients. Mixed-model analysis was used to compare the primary outcome of visual analog scale pain scores at 24 hours between groups. Forty-six patients were randomized, and 2 were excluded from analysis. The mean (95% confidence interval, CI) pain scores on movement at 24 hours were 21 mm (CI = 13-28) in the gabapentin and 41 mm (CI = 31-50) in the placebo group (P = 0.001). Maternal satisfaction was higher in the gabapentin group. There was no difference in opioid consumption. Severe maternal sedation was more common in the gabapentin group (19% vs. 0%, P = 0.04). There was no difference in neonatal Apgar scores, interventions, or umbilical artery pH. The mean (SD) maternal vein:umbilical vein plasma gabapentin ratio was 0.86 (0.12). The incidence of pain at 3 months was similar in both groups. Preoperative gabapentin 600 mg in the setting of multimodal analgesia reduces postcesarean delivery pain and increases maternal satisfaction in comparison with placebo.

A Comparison of the Pharmacokinetics and Pharmacodynamics of Pregabalin and Gabapentin

Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3-4 hours. Orally administered gabapentin exhibits saturable absorption--a nonlinear (zero-order) process--making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at > or = 90% irrespective of the dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.

The Effects of Intravenous Gabapentin Administration on the Minimum Alveolar Concentration of Isoflurane in Cats

Gabapentin is a structural analog of gamma-aminobutyric acid, one of the inhibitory neurotransmitters of the mammalian central nervous system. It is increasingly being used preemptively to control postoperative pain. Therefore, its interaction with inhaled anesthetics is of clinical interest. In this study, we examined the effects of gabapentin on the minimum alveolar concentration (MAC) of isoflurane in cats. We hypothesized that gabapentin would decrease the MAC of isoflurane in a dose-dependent manner. Six cats were included in the study. Gabapentin was administered IV to achieve target plasma concentrations between 0 and 16 microg/mL and the MAC of isoflurane was determined at each gabapentin concentration. Gabapentin concentrations were quantitated by liquid chromatography-mass spectrometry analysis of extracted plasma samples. MAC values at the different gabapentin plasma concentrations were analyzed by a repeated-measures analysis of variance using the Huynh-Feldt correction for violation of the sphericity assumption. Actual gabapentin concentrations were 0 + or - 0, 1.18 + or - 0.23, 2.25 + or - 0.23, 4.96 + or - 1.19, 10.63 + or - 1.37, and 19.69 + or - 3.97 microg/mL for the target concentrations of 0, 1, 2, 4, 8, and 16 microg/mL, respectively. The MAC of isoflurane in this study was 2.10% + or - 0.13%, 2.10% + or - 0.14%, 2.13% + or - 0.12%, 2.06% + or - 0.11%, 2.11% + or - 0.15%, and 2.09% + or - 0.25% at target plasma concentrations of 0, 1, 2, 4, 8, and 16 microg/mL, respectively. We conclude that gabapentin did not have a detectable effect on the MAC of isoflurane in cats.

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.

Suivi thérapeutique pharmacologique de la gabapentine

Gabapentin is a structural analogue of GABA used in the treatment of the partial epilepsies of adult and child of more than 12 years, in monotherapy or in association with other anticonvulsant drugs. In association, gabapentin presents the advantage of not interfering with the other anticonvulsant drugs. The interindividual pharmacokinetic variability and the saturable absorption are, with the adaptation in case of renal insufficiency, the only arguments in favor of TDM. During clinical studies, the plasma concentrations of gabapentin were generally included between 2 and 20 mg/L. For this molecule, the level of proof of the interest of therapeutic drug monitoring was estimated in: possibly useful.

Pharmacokinetics of oral gabapentin in greyhound dogs

The purpose of this study was to assess the pharmacokinetics of gabapentin in healthy greyhound dogs after single oral doses targeted at 10 and 20mg/kg PO. Six healthy greyhounds were enrolled (3 males, 3 females). Blood was obtained at predetermined times for the measurement of gabapentin plasma concentrations by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were determined with computer software. The actual mean (and range) doses administered were 10.2 (9.1-12.0) mg/kg and 20.5 (18.2-24) mg/kg for the 10mg/kg and 20mg/kg targeted dose groups. The mean C(MAX) for the 10 and 20mg/kg groups were 8.54 and 13.22 microg/mL at 1.3 and 1.5h, and the terminal half-lives were 3.3 and 3.4h, respectively. The relative bioavailability of the 10mg/kg group was 1.13 compared to the 20mg/kg group. Gabapentin was rapidly absorbed and eliminated in dogs, indicating that frequent dosing is needed to maintain minimum targeted plasma concentrations.

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

Background: Gabapentin absorption is mediated by a saturable transporter system located in the upper gastrointestinal tract, indicating a short window of absorption. Therefore, conventional sustained formulations would likely result in decreased bioavailability, as the dosage form would pass through the window of absorption before the drug could be completely released. Objective: The aim of this study was to compare the pharmacokinetics of an oral, gastric-retentive, gabapentin extended-release (G-ER) formulation with a gabapentin immediate-release (G-IR) formulation after single and multiple daily doses in healthy subjects. Methods: In this open-label, multiple-dose, 3-way crossover, exploratory study, healthy male and female subjects (aged 18-65 years) were randomized to receive doses of 1800 mg G-ER in accordance with the following regimens: G-ER QD (8 pm), G-ER BID in divided doses (600 mg at 8 am and 1200 mg at 8 pm), or G-IR TID (600 mg at 8 am, 2 pm, and 8 pm) on day 1 and on days 4 through 8 of each study period. The subjects underwent a 10-day washout between study periods. Gabapentin plasma concentrations were measured in serial plasma samples collected ≥48 hours following dosing on days 1 and 8 using a validated highperformance liquid chromatography/tandem mass spectrometry system with a lowest limit of quantitation of 75 ng/mL. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. Results: Of the 24 subjects enrolled in the study, 21 (11 males, 10 females; mean age, 37 years [range, 23- 60 years]; mean height, 172 cm [range, 158-188 cm], mean weight, 77 kg [range, 56-95 kg]; mean body mass index, 26.2 kg/m2 [range, 21.5-29.7 kg/m2]) completed the study. The completing subjects consisted of 8 whites, 7 blacks, 3 Asians, and 3 Hispanics. At steady state, exposure of both G-ER regimens (QD and BID) appeared similar compared with that of G-IR. However, BID dosing resulted in apparently lower C max (mean ratio: 81%; CI 90%, 76%-86%) and greater C min values (mean ratio: 118%; CI 90%, 107%-130%), while G-ER QD dosing was associated with numerically greater C max (mean ratio: 116%; CI 90%, 109%-123%), and lower C min values (mean ratio: 52%; CI 90%, 48%-56%) compared with G-IR TID during a 24-hour dosing period. A total of 47 treatment-emergent AEs occurred in 17 patients during the study. The most common AEs were headache (25% G-ER BID divided dose, 10% G-ER QD dosing, and 14% in G-IR TID dosing), dizziness (6%, 0%, and 19%), and muscle cramp (19%, 0%, and 10%). AEs were most prevalent in the G-IR study group. Conclusions: This exploratory study found that in these healthy subjects, the daily exposure provided by less frequent G-ER dosing was not significantly different from same daily dose with G-IR, administered more frequently. The G-ER BID dosing resulted in less fluctuation, while the G-ER QD dosing produced higher maximum concentrations compared with a G-IR TID regimen.

The Effects of Intravenous Lidocaine Administration on the Minimum Alveolar Concentration of Isoflurane in Cats

Lidocaine decreases the minimum alveolar concentration (MAC) of inhaled anesthetics and has been used clinically to reduce the requirements for other anesthetic drugs. In this study we examined the effects of lidocaine on isoflurane MAC in cats. Six cats were studied. In Experiment 1, the MAC of isoflurane was determined. An IV bolus of lidocaine 2 mg/kg was then administrated and venous plasma lidocaine concentrations were measured to determine pharmacokinetic values. In Experiment 2, lidocaine was administered to achieve target plasma concentrations between 1 and 11 microg/mL and the MAC of isoflurane was determined at each lidocaine plasma concentration. Actual lidocaine plasma concentrations were 1.06 +/- 0.12, 2.83 +/- 0.39, 4.93 +/- 0.64, 6.86 +/- 0.97, 8.86 +/- 2.10, and 9.84 +/- 1.34 microg/mL for the target concentrations of 1, 3, 5, 7, 9, and 11 microg/mL, respectively. The MAC of isoflurane in this study was 2.21% +/- 0.17%, 2.14% +/- 0.14%, 1.88% +/- 0.18%, 1.66% +/- 0.16%, 1.47% +/- 0.13%, 1.33% +/- 0.23%, and 1.06% +/- 0.19% at lidocaine target plasma concentrations of 0, 1, 3, 5, 7, 9, and 11 microg/mL, respectively. Lidocaine, at target plasma concentrations of 1, 3, 5, 7, 9, and 11 microg/mL, linearly decreased isoflurane MAC by -6% to 6%, 7% to 28%, 19% to 35%, 28% to 45%, 29% to 53%, and 44% to 59%, respectively. We conclude that lidocaine decreases the MAC of isoflurane.

The Use of Clinical Trial Simulation to Support Dose Selection: Application to Development of a New Treatment for Chronic Neuropathic Pain

Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated. A pharmacokinetic-pharmacodynamic (PK/PD) model relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to reflect pregabalin potency, which was based on preclincal data. Uncertainty about the potency difference and the steepness of the concentration-response slope necessitated simulating a distribution of outcomes for a series of PK/PD models. Analysis of the simulated data suggested that after accounting for the uncertainty, there was an 80% chance that the dose defining the clinical feature was within 45% of the true value. The likelihood of estimating a dose that was within an acceptable predefined precision range relative to a known value approximated 60%. The minimum dose that should be studied to have a reasonable chance of estimating the dose that caused a one-point change was 300 mg. Doses that identify predefined response may be imprecisely estimated, suggesting that replication of a similar outcome may be elusive in a confirmatory study. Quantification of this precision provides a rationale for phase 2 trial design and dose selection for confirmatory studies.

Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia.

Gabapentin and pregabalin are anticonvulsants with antihyperalgesic effects in animal models of neuropathic and inflammatory nociception. This study characterized the manner in which gabapentin or pregabalin interacts with naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan model of peripheral inflammation. Gabapentin, pregabalin, naproxen, or a fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was administered orally to rats after the induction of inflammation by intraplantar injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were determined by the radiant heat paw-withdrawal test. Paw edema was measured by plethysmometry. Drug plasma concentrations were determined by a liquid chromatography-mass spectroscopy-mass spectroscopy method. Gabapentin, pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of 19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen produced only additive effects. No combination of gabapentin + naproxen decreased paw edema in a manner greater than additive. Plasma concentrations of gabapentin and naproxen were unaltered by the addition of the other drug. The mixture of 10:1 of pregabalin + naproxen interacted synergistically to reverse thermal hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced additive effects. These data suggest that gabapentin + naproxen and pregabalin + naproxen can interact synergistically or additively to reverse thermal hyperalgesia associated with peripheral inflammation. Therefore, the use of gabapentin or pregabalin in low-dose combinations with naproxen may afford therapeutic advantages for clinical treatment of persistent inflammatory pain.

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind,...