Serum concentrations of gabapentin in cats with chronic kidney disease.

OBJECTIVES: The purpose of this study was to assess serum concentrations of gabapentin in cats with chronic kidney disease (CKD) vs clinically healthy cats. METHODS: Five healthy cats were enrolled in a pharmacokinetic study. A single 20 mg/kg dose of gabapentin was administered orally and blood was obtained at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24 and 36 h via a jugular catheter. Serum gabapentin concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Non-compartmental pharmacokinetic analysis was performed. The same five healthy cats plus 25 cats with stable International Renal Interest Society stage 2 (n = 14) and 3 (n = 11) CKD were enrolled in a limited sampling study. Cats in both groups received a single 10 mg/kg dose of gabapentin, and serum gabapentin concentrations and compliance scores were obtained 3 and 8 h post-administration. RESULTS: Cats with CKD had significantly higher dose-normalized serum gabapentin concentrations than normal cats at 3 h (P = 0.0012 CKD vs normal 10 mg/kg; P = 0.008 CKD vs normal 20 mg/kg) and 8 h (P <0.0001 CKD vs normal 10 mg/kg; P <0.0001 CKD vs normal 20 mg/kg). Both 3 and 8 h dose-normalized serum gabapentin concentrations were significantly correlated with serum creatinine (3 h: P = 0.03, r = 0.39; 8 h: P = 0.001, r = 0.57) and symmetric dimethylarginine (3 h: P = 0.03, r = 0.41; 8 h: P = 0.007, r = 0.48). There was a significant correlation between 3 h serum gabapentin concentrations and compliance scores (P = 0.0002, r = 0.68). CONCLUSIONS AND RELEVANCE: Cats with CKD that received 10 mg/kg of gabapentin had significantly higher dose-normalized serum concentrations than normal cats that received 20 mg/kg, supporting the need to dose-reduce in this patient population.

Gabapentinoid Pharmacology in the Context of Emerging Misuse Liability.

This article will review the epidemiology and pharmacology of gabapentinoids (gabapentin and pregabalin) relevant to their emerging misuse potential and provide guidance for clinical and regulatory management. Gabapentinoids are γ-aminobutyric acid analogues that produce their therapeutic effects by inhibiting voltage-gated calcium channels and decreasing neurotransmitter release. Recently gabapentinoid prescribing and use have increased tremendously. Although traditionally thought to possess a favorable safety profile, gabapentinoid misuse has also risen significantly. Gabapentinoid misuse generally occurs in combination with other substances, most notably opioids, and may be for purposes of eliciting euphoric effects, enhancing the effects of other substances, or self-treating conditions such as withdrawal, pain, anxiety, or insomnia. Given its faster onset, increased bioavailability and potency, and nonsaturable absorption, pregabalin's pharmacokinetics theoretically enhance its misuse liability versus gabapentin. However, gabapentin can produce similar euphoric effects, and epidemiologic studies have identified higher rates of gabapentin misuse in the United States, likely because of greater availability and less regulated prescribing. Although adverse events of gabapentinoid-only ingestion are relatively benign, a growing body of evidence indicates that gabapentinoids significantly increase opioid-related morbidity and mortality when used concomitantly. In addition, significant withdrawal effects may occur on abrupt discontinuation. As a result of these trends, several US states have begun to further regulate gabapentinoid prescribing, reclassifying it as a controlled substance or mandating reporting to local prescription drug-monitoring programs. Although increased regulation of gabapentin prescribing may be warranted, harm reduction efforts and increased patient and provider education are necessary to mitigate this concerning gabapentinoid misuse trend.

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations.

Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50 ] 237 µmol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2-K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.

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.

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

BACKGROUND: In 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 OBJECTIVES: Gabapentin 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. ANIMALS: Nine clinically healthy adult Arabian and Quarter Horses. METHODS: In 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. RESULTS: Plasma 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 IMPORTANCE: Gabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

Eficacia de pregabalina, gabapentina y duloxetina en el dolor neuropático verificado por el análisis de la curva-p / Efficacy of pregabalin, gabapentin and duloxetine in neuropathic pain verified by the p-curve analysis

INTRODUCCIÓN: Existe una preocupación creciente entre los clínicos y los investigadores de que muchos resultados publicados en revistas científicas se tratan de falsos positivos. OBJETIVO: Determinar el valor de evidencia o integridad del cuerpo de la literatura publicada sobre la eficacia de pregabalina, gabapentina y duloxetina en el tratamiento del dolor neuropático. MÉTODOS: Se realizó una búsqueda bibliográfica seleccionando ensayos clínicos aleatorizados que evaluaban la eficacia de pregabalina, gabapentina y duloxetina en dolor neuropático. Se aplicó el análisis de curva-p de los estudios con resultados estadísticamente significativos para estudiar su distribución. RESULTADOS: Se demostró que existía una asimetría significativa a la derecha en la curva-p de los tres fármacos (test continuo p < 0,0001) confirmando el valor de evidencia de los estudios. CONCLUSIONES: Los clínicos, los científicos y las publicaciones científicas deben ser conscientes del problema creciente con el "p-hacking" y sus efectos perjudiciales. Todas las partes comparten la responsabilidad en mantener la integridad científica de la literatura publicada

INTRODUCTION: There is a growing concern among clinicians and researchers that many results published in scientific journals are false positives. OBJECTIVE: To determine the value of evidence or integrity of the body of the published literature on the efficacy of pregabalin, gabapentin and duloxetine in the treatment of neuropathic pain. METHODS: A literature search was conducted selecting randomized clinical trials that evaluated the efficacy of pregabalin, gabapentin and duloxetine in neuropathic pain. The p-curve analysis of the studies with statistically significant results was applied to study their distribution. RESULTS: It was demonstrated that there was a significant asymmetry to the right in the p-curve of the three drugs (continuous test p <0.0001) confirming the value of evidence from the studies. CONCLUSIONS: Clinicians, scientists and scientific publications should be aware of the growing problem with "p-hacking" and its harmful effects. All parties share the responsibility to maintain the scientific integrity of the published literature

Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial.

BACKGROUND: Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. METHODS/DESIGN: The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. DISCUSSION: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. TRIAL REGISTRATION: EudractCT, 2014-004897-40 . Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012 . Registered on 7 September 2017.

Switchability of Gabapentin Formulations: A Randomized Trial to Assess Bioequivalence Between Neurontin and Gabasandoz on the Individual Subject Level.

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800 mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between-batch and between-formulation variability in exposure play a significant role in the within-subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being -2.01 and -2.31 for area under the concentration-time curve from zero to infinity (AUC0-inf ) and peak plasma concentration (Cmax ), respectively. Subject-by-formulation variability (1.35%) was negligible compared with the within-subject variability of AUC0-inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within-subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800 mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method to Quantify Gabapentin and Pregabalin in Urine.

Gabapentin and pregabalin are anticonvulsant drugs that are also utilized for pain management. A mass spectrometry method was developed and validated to quantify gabapentin and pregabalin in urine to support testing for adherence.

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

Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role in GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from 53 patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy-Weinberg equilibrium. An one-compartment model with first-order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution, and clearance estimated were 0.44 h-1 , 86 L, and 17.3 × (estimated glomerular filtration ratio/89.58)1.04  L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism.

Prediction of the Oral Pharmacokinetics and Food Effects of Gabapentin Enacarbil Extended-Release Tablets Using Biorelevant Dissolution Tests.

The purpose of this research was to establish an in vitro dissolution testing method to predict the oral pharmacokinetic (PK) profiles and food effects of gabapentin enacarbil formulated as wax matrix extended-release (ER) tablets in humans. We adopted various biorelevant dissolution methods using the United States Pharmacopeia (USP) apparatus 2, 3 and 4 under simulated fasted and fed states. Simulated PK profiles using the convolution approach were compared to published in vivo human PK data. USP apparatus 2 and 4 underestimated the in vivo performance due to slow in vitro dissolution behaviors. In contrast, biorelevant dissolution using USP apparatus 3 coupled with the convolution approach successfully predicted the oral PK profile of gabapentin enacarbil after oral administration of a Regnite® tablet under fasted state. This approach might be useful for predicting the oral PK profiles of other drugs formulated as wax matrix-type ER tablets under fasted state.

The pharmacokinetics of gabapentin in cats.

BACKGROUND: Gabapentin 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. OBJECTIVES: To evaluate the pharmacokinetics of clinically relevant dosing regimens of gabapentin in cats. ANIMALS: Eight research-purpose mixed-breed cats. METHODS: Cats 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. RESULTS: After 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). IMPORTANCE: Repeated 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.

PHARMACOKINETICS OF ORAL GABAPENTIN IN CARIBBEAN FLAMINGOS ( PHOENICOPTERUS RUBER RUBER).

Gabapentin is a first-line treatment for neuropathic pain and adjunct anticonvulsant medication in humans and other species. Gabapentin may have advantages over other analgesics because of its broad therapeutic range with limited adverse effects and wide availability as an oral formulation. This study determined the pharmacokinetics of gabapentin in Caribbean flamingos ( Phoenicopterus ruber ruber) after a single-dose oral administration of either 15 mg/kg ( n = 6) or 25 mg/kg ( n = 6). Plasma gabapentin concentrations were determined using liquid chromatography with mass spectrometry, and pharmacokinetic analysis was performed using noncompartmental methods. Respectively for the 15 mg/kg and 25 mg/kg dose, mean peak plasma concentration ( Cmax) was (mean ± pseudo SD) 13.23 ± 1.47 and 24.48 ± 5.81 µg/ml; mean time to peak plasma concentration ( Tmax) was 0.50 ± 0.24 and 0.56 ± 0.28 hr; mean area under the curve (AUC) was 76.0 ± 26.3 and 114.7 ± 27.5 hr·µg/ml; and mean terminal half-life ( T1/2) was 3.39 ± 0.90 and 4.46 ± 1.12 hr. Based on the results of this study, gabapentin dosed at 25 mg/kg orally in most Caribbean flamingos is likely to maintain plasma concentrations above the therapeutic range established for humans for approximately 12 hr.

Role of l-Type Amino Acid Transporter 1 at the Inner Blood-Retinal Barrier in the Blood-to-Retina Transport of Gabapentin.

Gabapentin is an antiseizure drug that is known to also have beneficial effects on the retinal cells. To use gabapentin in retinal pharmacotherapy, it is critical to understand gabapentin distribution in the retina. The purpose of this study was to clarify the kinetics of gabapentin influx transport across the inner and outer blood-retinal barrier (BRB), which regulates the exchange of compounds/drugs between the circulating blood and the retina. In vivo blood-to-retina gabapentin transfer was evaluated by the rat carotid artery injection technique. In addition, gabapentin transport was examined using in vitro models of the inner (TR-iBRB2 cells) and outer BRB (RPE-J cells). The in vivo [3H]gabapentin transfer to the rat retina across the BRB was significantly reduced in the presence of unlabeled gabapentin, suggesting transporter-mediated blood-to-retina distribution of gabapentin. Substrates of the Na+-independent l-type amino acid transporter 1 (LAT1), such as 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), also significantly inhibited the in vivo [3H]gabapentin transfer. [3H]Gabapentin uptake in TR-iBRB2 and RPE-J cells exhibited Na+-independent and saturable kinetics with a Km of 735 and 507 µM, respectively. Regarding the effect of various transporter substrates/inhibitors on gabapentin transport in these cells, LAT1 substrates significantly inhibited [3H]gabapentin uptake in TR-iBRB2 and RPE-J cells. In addition, preloaded [3H]gabapentin release from TR-iBRB2 and RPE-J cells was trans-stimulated by LAT1 substrates through the obligatory exchange mechanism as LAT1. Immunoblot analysis indicates the protein expression of LAT1 in TR-iBRB2 and RPE-J cells. These results imply that LAT1 at the inner and outer BRB takes part in gabapentin transport between the circulating blood and retina. Moreover, treatment of LAT1-targeted small interfering RNA to TR-iBRB2 cells significantly reduced both the level of LAT1 protein expression and [3H]gabapentin uptake activities in TR-iBRB2 cells. In conclusion, data from the present study indicate that LAT1 at the inner BRB is involved in retinal gabapentin transfer, and also suggest that LAT1 mediates gabapentin transport in the RPE cells.

Interchangeability of Generic Drugs: A Nonparametric Pharmacokinetic Model of Gabapentin Generic Drugs.

Substitution by generic drugs is allowed when bioequivalence to the originator drug has been established. However, it is known that similarity in exposure may not be achieved at every occasion for all individual patients when switching between formulations. The ultimate aim of our research is to investigate if pharmacokinetic subpopulations exist when subjects are exposed to bioequivalent formulations. For that purpose, we developed a pharmacokinetic model for gabapentin, based on data from a previously conducted bioavailability study comparing gabapentin exposure following administration of the gabapentin originator and three generic gabapentin formulations in healthy subjects. Both internal and external validation confirmed that the optimal model for description of the gabapentin pharmacokinetics in this comparative bioavailability study was a two-compartment model with absorption constant, an absorption lag time, and clearance adjusted for renal function, in which each model parameter was separately estimated per administered formulation.