Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults
.

OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
.

Drugging the undruggable: gabapentin, pregabalin and the calcium channel α2δ subunit.

In the post-genomic era, the idea of using the sequence of a protein to determine its potential role as a drug target has gained currency. The goal of this approach to drug discovery is to use the sequence of a protein that is known to bind a specific ligand or drug, along with the known structure of the ligand binding site, to predict other similar proteins that are also "druggable". Gabapentin (Neurontin) and pregabalin (Lyrica) are drugs currently in the clinic that were developed based on the hypothesis that generating non-hydrolyzable analogs of GABA would lead to the development of antiepileptic agents. While these compounds are indeed good anticonvulsants, their activity is surprisingly not due to activity in the GABAergic system. By purifying the protein to which gabapentin bound, and determining its identity as the α2δ1 subunit of voltage gated calcium channels, it was possible to make progress in developing new compounds with similar activities to gabapentin, including pregabalin. The recognition of the α2δ1 subunit as the receptor for these drugs also meant that related proteins, such as α2δ3, may be interesting targets for novel pain therapeutics.

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 800 mg). 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 0.860 h-1, and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. 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.

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.

BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

Population Pharmacokinetic Modelling of Morphine, Gabapentin and their Combination in the Rat.

PURPOSE: The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles. METHODS: The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions. RESULTS: The plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation. CONCLUSIONS: The finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.

Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.

PURPOSE: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. METHODS: A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). RESULTS: The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m = 44.1 mg/kg, V max = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma = 16.7 µg/mL, EC 50, brain = 3.3 µg/mL). CONCLUSIONS: The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center.

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (-325 pmol/l, p=0.09) and number of retrieved oocytes (-1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health.

Noninvasive sampling of gabapentin by reverse iontophoresis.

PURPOSE: Transdermal reverse iontophoresis offers a noninvasive tool for clinical and therapeutic monitoring of drugs and endogenous molecules. This study investigated the viability of reverse iontophoresis as an alternative technique to blood sampling for the monitoring of gabapentin. METHODS: Ex vivo studies assessed the influence of polarity, applied current (0.064-0.32 mA) and subdermal concentration (0.5-20 µg/mL) on the recovery of gabapentin. These experiments were carried out in vertical Franz diffusion cell for a period of 3 h using rat skin. In vivo experiments examined the versatility of this method to extract gabapentin from the subdermal region following intravenous administration of gabapentin (30 mg/kg) in rat model. RESULTS: Preliminary studies demonstrate that greater amount of gabapentin was extracted in the cathodal chamber due to the contribution of electroosmosis. Increasing the current intensity significantly enhances the extraction flux (P < 0.005) and shown linear relation (r(2) = 0.84) between the applied electrical dose (mA*h) and the amount of gabapentin recovered (µg). Indeed, transdermal iontophoresis of gabapentin was found to be concentration dependent in the range studied (0.5-20 µg/mL), which includes clinically relevant level. Further, a linear relationship was established between the iontophoretically recovered gabapentin 3 h flux values and the subdermal concentrations studied. The linear correlation with good regression value (r(2) = 0.92) observed in the in vivo studies infers that the drug in the plasma is proportionally extracted through the skin and potentially represents the subdermal drug concentrations. CONCLUSIONS: Given the promising results, this study concludes that the transdermal reverse iontophoresis technique could be a promising alternative for the noninvasive monitoring of gabapentin.

In vivo and in vitro evaluations of intestinal gabapentin absorption: effect of dose and inhibitors on carrier-mediated transport.

PURPOSE: Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations METHODS: Pharmacokinetic parameters were determined following a range of intravenous (5-100 mg/kg) and oral doses (10-200 mg/kg) in rats. Transepithelial transport (50 µM-50 mM) and apical uptake of gabapentin (0.01-50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b(0,+)-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro. RESULTS: Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine. CONCLUSIONS: The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.

Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution.

CONTEXT: Gabapentin was selected to formulate oral controlled release dry suspension because of short biological half life of 5-7 h and low bioavailability (60%). Gabapentin is a bitter drug so an attempt was made to mask its taste. OBJECTIVE: To formulate and evaluate controlled release dry suspension for reconstitution to increase the bioavailability and to control bitter taste of drug. MATERIALS AND METHODS: Cyclodextrin based nanosponges were synthesized by previously reported melt method. The nanosponge-drug complexes were characterized by FTIR, DSC and PXRD as well as evaluated for taste and saturation solubility. The complexes were coated on Espheres by a suspension layering technique followed by coating with ethyl cellulose and Eudragit RS-100. A dry powder suspension for reconstitution of the microspheres was formulated and evaluated for taste, redispersibility, in vitro dissolution, sedimentation volume, leaching and pharmacokinetics. RESULTS AND DISCUSSION: The complexes showed partial entrapment of drug nanocavities. Significant decrease in solubility (25%) was observed in the complexes than pure drug in different media. The microspheres of nanosponge complexes showed desired controlled release profile for 12 h. Insignificant drug leaching was observed in reconstituted suspension during storage for 7 days at 45 °C/75% RH. Nanosponges effectively masked the taste of Gabapentin and the coating polymers provided controlled release of the drug and enhanced taste masking. The results of in vivo studies showed increase in bioavailability of controlled release suspension by 24.09% as compared to pure drug. CONCLUSION: The dry powder suspension loaded with microspheres of nanosponges complexes can be proposed as a suitable controlled release drug delivery for Gabapentin.

PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 µg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 µg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 µg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls.

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.

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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Semi-mechanistic modelling of the analgesic effect of gabapentin in the formalin-induced rat model of experimental pain.

PURPOSE: The formalin-induced rat model of nociception involves moderate continuous pain. Formalin-induced pain results in a typical repetitive flinching behaviour, which displays a biphasic pattern characterised by peaks of pain. Here we described the time course of pain response and the analgesic effect of gabapentin using a semi-mechanistic modelling approach. METHODS: Male Sprague-Dawley rats received gabapentin (10-100 mg/kg) or placebo 1 h prior to the formalin injection, as per standard protocol. A reduction in the frequency of the second peak of flinching was used as a behavioural measure of gabapentin-mediated anti-nociception. The flinching response was modelled using a mono-exponential function to characterise the first peak and an indirect response model with a time variant synthesis rate for the second. PKPD modelling was performed using a population approach in NONMEM v.7.1.2. RESULTS: The time course of the biphasic response was adequately described by the proposed model, which included separate expressions for each phase. Gabapentin was found to reversibly decrease, but not suppress the flinching frequency of the second response peak only. The mean IC50 estimate was 7,510 ng/ml, with relative standard error (RSE%) of 40%. CONCLUSIONS: A compartmental, semi-mechanistic model provides the basis for further understanding of the formalin-induced flinching response and consequently to better characterisation of the properties of gabapentin, such as the potency in individual animals. Moreover, despite high exposure levels, model predictions show that gabapentin does not completely suppress behavioural response in the formalin-induced pain model.

Derivation of an oral reference dose (RfD) for the nonphthalate alternative plasticizer 1,2-cyclohexane dicarboxylic acid, di-isononyl ester (DINCH).

1,2-Cyclohexanedicarboxylic acid, 1,2-diisononylester (DINCH), a polyvinyl chloride plasticizer, has food, beverage, and medical device applications that may result in general population exposure. Although no apparent toxicity information in humans was identified, there is a substantial data set in lab animals to serve as the basis of hazard identification for DINCH. Target tissues associated with repeated dietary DINCH exposure in lab animals included liver, kidney, and thyroid and mammary glands. In contrast to some phthalate ester plasticizers, DINCH did not show evidence of hepatic peroxisomal proliferation, testicular toxicity, or liver tumors in rats. Liver and thyroid effects associated with DINCH exposure were attributed to compensatory thyroid stimulation secondary to prolonged metabolic enzyme induction. The toxicological significance of mammary fibroadenomas in female rats is unclear, given that this common benign and spontaneously occurring tumor type is unique to rats. The weight of evidence suggests DINCH is not genotoxic and the proposed mode of action (MOA) for thyroid gland lesions was considered to have a threshold. No adverse reproductive effects were seen in a two-generation study. An oral reference dose (RfD) of 0.7 mg/kg-d was derived from a human equivalent BMDL10 of 21 mg/kg-d for thyroid hypertrophy/hyperplasia seen in adult F1 rats also exposed in utero. The total uncertainty factor of 30x was comprised of intraspecies (10×) and database (3×) factors. An interspecies extrapolation factor was not applied since rodents are more sensitive than humans with respect to the proposed indirect MOA for thyroid gland lesions.

Human skin absorption of three plasticizers: Diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA).

Alternative plasticizers such as diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA) are progressively replacing phthalates in many consumer and professional products because of adverse effects on reproduction associated with some phthalates. Human exposures to these phthalate substitutes can occur through ingestion, skin absorption and inhalation. Skin uptake can lead to greater concentration at the target organs compared to ingestion because the skin exposure route bypasses the first-pass effect. Skin absorption studies are almost absent for these alternative plasticizers. We therefore wanted first, to characterize skin absorption of a mixture containing DINCH, DEHA and DEHTP in vitro using a flow-through diffusion cell system with ex vivo human skin, quantifying their respective monoester metabolites (mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH), mono-2-ethylhexyl adipate (MEHA), mono-2-ethylhexyl terephthalate (MEHTP), respectively); second, to validate these results by exposing five human volunteers to this mixture on their forearm and quantifying the corresponding urinary metabolites (including the monoesters and their oxidation products). Our study showed that two of these alternative plasticizers, DEHTP and DINCH, did not permeate skin showing as quantifiable metabolite levels in vitro and only traces of DEHA were quantified as its monoester metabolite, MEHA. Permeation coefficient (Kp) 0.06 and 55.8*10-7 cm/h for neat and emulsified DEHA, respectively, while the permeation rate (J) remained low for both (0.005 and 0.001 µg/cm2/h, respectively). Participants exposed to a mixture of these three plasticizers did not have noteworthy urinary concentrations of their respective metabolites after 24 hours post-application. However, the alternative plasticizer mixture was completely absorbed after six hours post-application on the forearms of the human volunteers, and the urinary elimination curves showed a slight increase after 24 hours post-application. Further studies on skin absorption of these substances should follow the urinary elimination kinetics of these metabolites more than 24 hours post-application. We also recommend quantifying the parent compounds in the in vitro diffusion experiments.

Gabapentin to pregabalin therapy transition: a pharmacokinetic simulation.

The objective of this modeling study was to assess different dosage regimens that might be used to guide clinicians in transitioning patients from gabapentin to pregabalin therapy when such a transition is clinically warranted. Two different gabapentin to pregabalin transition designs were simulated based on their respective population pharmacokinetic profiles. The first design involved immediate discontinuation of gabapentin therapy with initiation of pregabalin therapy at the next scheduled dose period. The second design featured a gradual transition involving coadministration of 50% of the gabapentin dosage and 50% of the desired pregabalin dosage for 4 days, followed by discontinuation of gabapentin and fully targeted dosages of pregabalin. Both transition designs were studied at 3 dosage levels: gabapentin 900 mg/d to pregabalin 150 mg/d, gabapentin 1800 mg/d to pregabalin 300 mg/d, and gabapentin 3600 mg/d to pregabalin 600 mg/d. Overall drug exposure achieved during the 2 transition designs was the sum of the gabapentin and pregabalin concentrations, expressed as pregabalin-equivalent concentrations. The pharmacokinetic simulations show that during the transition period in both designs, predicted pregabalin-equivalent concentrations did not depart from those calculated during periods of steady-state gabapentin or pregabalin monotherapy. Transition from gabapentin to pregabalin was seamless and rapid, with predicted pregabalin-equivalent concentrations highly comparable with plasma pregabalin concentrations within 1 day of pregabalin initiation in the immediate discontinuation model and within 1 day of gabapentin cessation in the gradual discontinuation model. These data suggest that transitioning patients from gabapentin to pregabalin could theoretically be achieved by either of the 2 approaches assessed.

A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid.

We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 µg/mL; JP2, 462 µg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.

Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil.

BACKGROUND: Gabapentin exposure following administration of certain doses of gabapentin or its pro-drug gabapentin enacarbil has been previously reported in the literature, with variable results. METHODS: Meta-analyses of dose-exposure relationships were conducted to maximise precision and minimise bias. Study-level mean data for gabapentin systemic exposure, in terms of bioavailable dose and steady-state average plasma concentration, were modelled as a function of daily dose. Several linear and non-linear candidate models were tested. RESULTS: An Emax model best described the dose-exposure relationships for gabapentin. The ED50 was 3,080 mg/day for bioavailable dose or 3,370 mg/day for steady-state concentration; and the maximum exposure was 2,340 mg/day or 16.9 mg/L. For gabapentin enacarbil, a power model was most suitable, with a power of 0.925 for bioavailable dose or 0.844 for steady-state concentration. All parameters were estimated with < 20 % standard error. Simulations confirmed that these models accurately reflected the distribution of the respective data, and bootstrapping showed high precision for the estimated dose-exposure curves. CONCLUSION: The meta-analyses addressed issues associated with between-study variability; and confirmed the highly non-linear nature of dose-exposure relationships for gabapentin and the essentially linear relationships for gabapentin enacarbil. The resulting models could be used to simulate exposure at any clinically relevant dose and bridge therapeutic dose range between the two drugs.

Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH(®)) in humans after single oral doses.

Hexamoll(®) DINCH(®) (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH(®) was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll(®) DINCH(®) (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC-MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0-26.5 %). 14.8 % (11.3-16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7-12.9 %), oxo-MINCH 2.0 % (1.5-2.6 %) and carboxy-MINCH 2.0 % (1.8-2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9-42.4 %) of the DINCH(®) dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH(®) exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH(®) intakes based on these metabolites in environmental and occupational studies.