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 subcutaneous ketamine administration via the Omnipod® system in dogs.

Ketamine is an injectable anesthetic agent with analgesic and antidepressant effects that can prevent maladaptive pain. Ketamine is metabolized by the liver into norketamine, an active metabolite. Prior rodent studies have suggested that norketamine is thought to contribute up to 30% of ketamine's analgesic effect. Ketamine is usually administered as an intravenous (IV) bolus injection or continuous rate infusion (CRI) but can be administered subcutaneously (SC) and intramuscularly (IM). The Omnipod® is a wireless, subcutaneous insulin delivery device that adheres to the skin and delivers insulin as an SC CRI. The Omnipod® was used in dogs for postoperative administration of ketamine as a 1 mg/kg infusion bolus (IB) over 1 hour (h). Pharmacokinetics (PK) showed plasma ketamine concentrations between 42 and 326.1 ng/mL. The median peak plasma concentration was 79.5 (41.9-326.1) ng/mL with a Tmax of 60 (30-75) min. After the same infusion bolus, the corresponding norketamine PK showed plasma drug concentrations between 22.0 and 64.8 ng/mL. The median peak plasma concentration was 43.0 (26.1-71.8) ng/mL with a median Tmax of 75 min. The median peak ketamine plasma concentration exceeded 100 ng/mL in dogs for less than 1 h post infusion. The Omnipod® system successfully delivered subcutaneous ketamine to dogs in the postoperatively.

Sampling Site Has a Critical Impact on Physiologically Based Pharmacokinetic Modeling.

It has been shown that arterial (central) and venous (peripheral) plasma drug concentrations can be very different. While pharmacokinetic studies typically measure drug concentrations from the peripheral vein such as the arm vein, physiologically based pharmacokinetic (PBPK) models generally output simulated concentrations from the central venous compartment that physiologically represents the right atrium, a merge of the superior and inferior vena cava. In this study, a physiologically based peripheral forearm sampling site model was developed and verified using nicotine, ketamine, lidocaine, and fentanyl as model drugs. This verified model allows output of simulated peripheral venous concentrations that can be meaningfully compared with observed pharmacokinetic data from the arm vein. The generalized effect of PBPK model sampling site on simulation output was investigated. Drugs and metabolites with large volumes of distribution showed considerable concentration discrepancy between the simulated central venous compartment and the peripheral arm vein after intravenous or oral administration, resulting in significant differences in values for C max and time taken to reach C max (t max ) In addition, the simulated central venous metabolite profile showed an unexpected profile that was not observed in the peripheral arm vein. Using fentanyl as a model compound, we show that using the wrong sampling site in PBPK models can lead to biased model evaluation and subsequent erroneous model parameter optimization. Such an error in model parameters along with the discrepant sampling site could dramatically mislead the pharmacokinetic prediction in unstudied clinical scenarios, affecting the assessment of drug safety and efficacy. Overall, this study shows that PBPK model publications should specify the model sampling sites and match them with those employed in clinical studies. SIGNIFICANCE STATEMENT: Our study shows that sampling from the central venous compartment (right atrium) during physiologically based pharmacokinetic model development gives rise to biased model evaluation and erroneous model parameterization when observed data are collected from the peripheral arm vein. This can lead to a clinically significant error in predictions of plasma concentration-time profiles in unstudied scenarios. To address this error, we developed and verified a novel peripheral sampling site model to simulate arm vein drug concentrations that can be applied to different drug dosing scenarios.

Pharmacokinetic study of eight bioactive components following oral administration of Zhiqiao Gancao decoction and observation of its clinical efficacy.

Zhiqiao Gancao (ZQGC) decoction is widely used in China due to its therapeutic effect on lumbar disc herniation (LDH). In this study, we compared the clinical therapeutic effects among oral ZQGC decoction treatment, bed rest, and oral anti-inflammatory drug celecoxib treatment using visual analog scale, Oswestry Disability Index, and MacNab scores. The results showed that ZQGC decoction can significantly improve the symptoms of patients with LDH. A selective, sensitive, and rapid ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of eight bioactive components in rat plasma. The plasma samples were extracted by simple protein precipitation with methanol. The protonated analytes were quantitated simultaneously in positive and negative ion modes by multiple reaction monitoring with a mass spectrometer. The calibration curve of eight components in plasma showed good linearity (r > .996) and the extraction recovery was 81.19% ± 2.15% - 100.39 ± 3.36 (relative standard deviation: 1.21%-10.70%). The accuracy of all the lower limit of quantitation values was quantified within 80%-120%, and the precision was less than 15%. This validated method was successfully applied to the pharmacokinetics study in rat plasma after ZQGC decoction oral treatment. Our research can provide experimental basis for the rational clinical application of ZQGC decoction in the treatment of LDH.

Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist.

EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2 R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single 14 C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.

A screen-printed electrochemical sensing platform surface modified with nanostructured ytterbium oxide nanoplates facilitating the electroanalytical sensing of the analgesic drugs acetaminophen and tramadol.

An electrochemical sensing platform based upon screen-printing electrodes (SPEs) modified with nanostructured lanthanide metal oxides facilitate the detection of the widely misused drugs acetaminophen (ACP) and tramadol (TRA). Among the metal oxides examined, Yb2O3 nanoplates (NPs) were found to give rise to an optimal electrochemical response. The electroanalysis of ACP and TRA individually, and within mixtures, was performed using cyclic and differential pulse voltammetry. The ACP and TRA exhibited non-overlapping voltammetric signals at voltages of +0.30 and + 0.67 V (vs. Ag/AgCl; pH 9) using Yb2O3-SPEs. Pharmaceutical dosage forms and spiked human fluids were analyzed in wide linear concentration ranges of 0.25-654 and 0.50-115 µmol.L-1 with limits of detection (LOD) of 55 and 87 nmol.L-1 for ACP and TRA, respectively. The Yb2O3-SPEs offer a sensitive and chemically stable enzyme-free electrochemical platform for ACP and TRA assay. Graphical abstractSchematic presentation of one-shot electrochemical analysis of misused drugs, tramadol (TRA) and acetaminophen (ACP) by utilizing ytterbium oxide nanoplates modified screen-printed electrodes (Yb2O3-SPEs). The Yb2O3-SPEs showed interesting responses for ACP and TRA within pharmaceutical formulations and human fluids.

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats.

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration-time curve (AUC0-∞ ), elimination half-life (t1/2ʎz ), total clearance (ClT ) and volume of distribution at steady state (Vdss ) were 6.64 ± 0.81 hr* µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h-1  kg-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t1/2ʎz , increased dose-normalized AUC0-∞ , and decreased ClT . In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.

Pharmacokinetics of tolfenamic acid in green sea turtles (Chelonia mydas) after intravenous and intramuscular administration.

The present study aimed to evaluate the pharmacokinetic features of tolfenamic acid (TA) in green sea turtles, Chelonia mydas. Green sea turtles were administered single either intravenous (i.v.) or intramuscular (i.m.) injection of TA, at a dose of 4 mg/kg body weight (b.w.). Blood samples were collected at preassigned times up to 168 hr. The plasma concentrations of TA were measured using a validated liquid chromatography tandem mass spectrometry method. Tolfenamic acid plasma concentrations were quantifiable for up to 168 hr after i.v. and i.m. administration. The concentration of TA in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 55.01 ± 8.34 µg/ml following i.m. administration. The elimination half-life values were 32.76 ± 4.68 hr and 53.69 ± 3.38 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 72.02 ± 10.23%, and the average binding percentage of TA to plasma protein was 19.43 ± 6.75%. Based on the pharmacokinetic data, the i.m. administration of TA at a dosage of 4 mg/kg b.w. might be sufficient to produce a long-lasting anti-inflammatory effect (7 days) for green sea turtles. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Population pharmacokinetic modelling and simulation of fremanezumab in healthy subjects and patients with migraine.

AIMS: Fremanezumab is a fully humanized IgG2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability. METHODS: Nonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks. RESULTS: A 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658. CONCLUSIONS: A comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.

Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study.

PURPOSE: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months. METHODS: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. RESULTS: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUCref (80-125% range 39.2-61.2 mg/L/h). AUC0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. CONCLUSIONS: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02660177 .

Pharmacokinetics of ketorolac in wild Eastern box turtles (Terrapene carolina carolina) after single intramuscular administration.

Ketorolac is a nonsteroidal anti-inflammatory drug that possesses potent analgesic activity comparable to morphine. The opioid shortage in the United States has led to an unreliable supply of opioids for use in rehabilitation facilities, thus underscoring the need for research on the safe and effective use of nonopioid alternatives. The goal of this study was to determine the pharmacokinetics of ketorolac after a single 0.25 mg/kg intramuscular injection administered to injured Eastern box turtles (Terrapene carolina carolina). A sparse blood sampling protocol was used to collect samples from 32 wild turtles that presented to the Turtle Rescue Team at North Carolina State University for traumatic injuries. Blood was collected from 0 to 24 hr after injection and analyzed via high-pressure liquid chromatography (HPLC). A nonlinear mixed-effects (NLME) model was fitted to the data to obtain typical values for population parameters. Using this approach, we identified a long half-life (T1/2 ) of 9.78 hr and a volume of distribution (Vss ) of 0.26 L/kg. We have concluded that this long T1/2 for a dose of 0.25 mg/kg ketorolac-injected IM provides plasma levels above a previously published target level for 24-hour analgesia to allow for once daily dosing.

Pharmacokinetics of tolfenamic acid in red-eared slider turtles (Trachemys scripta elegans).

OBJECTIVE: To determine the pharmacokinetics of tolfenamic acid (TA) after different routes of administration [intravenous (IV) and intramuscular (IM), 2 mg kg-1] and doses (IV, 2 and 4 mg kg-1) in red-eared slider turtles (Trachemys scripta elegans). STUDY DESIGN: Randomized experimental trial. ANIMALS: Sixteen healthy red-eared slider turtles. METHODS: Turtles were randomly assigned to two groups (n = 8 each). Group 1 received TA at a dose of 2 mg kg-1 IV and then IM, after a washout period of 30 days. Group 2 received 4 mg kg-1 TA IV. A noncompartmental analysis was used to calculate pharmacokinetic variables. RESULTS: No local and/or systemic adverse drug effects were observed in any turtle. Elimination half-life and mean residence time following IM administration at 2 mg kg-1 were significantly longer than those following IV administration. The bioavailability following IM administration was complete. The area under the plasma concentration-time curve, elimination half-life, mean residence time and total clearance were significantly different between the dose groups. CONCLUSIONS AND CLINICAL RELEVANCE: The absence of adverse reactions in the turtles of the study of TA along with the favourable pharmacokinetic properties (the long half-life and the complete bioavailability) of TA administered at the single doses of 2 and 4 mg kg-1 suggest the possibility of its effective use in turtles. However, further studies are required to establish a multiple dosage regimen of TA and to evaluate the clinical efficacy of administering TA.

A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb® Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects.

Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0-8h/AUC0-24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration.

Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(-) Ketamine Concentrations.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. METHODS: S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. RESULTS: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(-) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(-) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. CONCLUSIONS: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

The detection of capsaicin and dihydrocapsaicin in horse serum following long-term local administration.

BACKGROUND: Capsaicin and dihydrocapsaicin are alkaloids with analgesic effects in humans and animals. When used locally, both of them minimalise pain sensation by defunctionalising nerve endings. According to the Federation Equestrian International Prohibited Substances List, these are substance banned in horse competitions. The aim of the study was to determine the detection time of capsaicin in both plasma and serum after long-term use of a gel recommended for commercial use and applied as intended. The objective of the study was to select the best material for the detection of capsaicin as a doping substance in horses. METHODS: Nine healthy mature horses were administered 0.1% capsaicin topically in the form of a commercial analgesic gel (15 g of the gel per limb) to the front limbs every 24 hours for five days with a polar fleece bandage. Blood serum and plasma were collected prior to gel application and in the 12th, 18th, 24th, 36th, 42nd, 48th, 60th, 84th, 108th, 132nd, 156th hour after the gel application. Qualitative and quantitative analysis was performed using ultra-high performance liquid chromatography coupled with a triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS). RESULTS: The concentration of capsaicin in the serum samples did not exceed the lower limit of quantification. Capsaicin was not detected in the plasma samples during the entire study period. Dihydrocapsaicin was not detected in blood serum or plasma. CONCLUSION: The presented results suggest that capsaicin is not detected in horse serum in the 24-hour-periodfollowing its last application according to the dosage regimen used by owners and veterinarians for therapy rather than doping, based on a five day gel application and a polar bandage.

In Vitro Adsorption of Analgosedative Drugs in New Extracorporeal Membrane Oxygenation Circuits.

OBJECTIVE: Evaluate drug disposition of sedatives and analgesics in the Xenios/Novalung extracorporeal membrane oxygenation circuits. DESIGN: In vitro experimental study. SETTING: Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. SUBJECTS: Nine closed-loop extracorporeal membrane oxygenation circuits, made up of the iLA Activve console with four different iLA Activve kits: two X-lung kits, two iLA-Activve iLA kits, two MiniLung kits, and three MiniLung petite kits. INTERVENTIONS: The circuits were primed with fresh whole blood and maintained under physiologic conditions (pH/temperature) throughout 24 hours. Paracetamol, morphine, midazolam, fentanyl, and sufentanil were injected as standard age-related doses into nine closed-loop extracorporeal membrane oxygenation circuits. MEASUREMENTS AND MAIN RESULTS: Pre-membrane (P2) blood samples were obtained prior to drug injection and after injection at 2, 10, 30, 180, 360 minutes, and at 24 hours. A control sample at 2 minutes was collected for spontaneous drug degradation testing at 24 hours. Two hundred sixteen samples were analyzed. After correction for the spontaneous drug degradation, the mean drug loss at 24 hours was paracetamol 49%, morphine 51%, midazolam 40%, fentanyl 84%, sufentanil 83%. Spontaneous degradation was paracetamol 6%, morphine 0%, midazolam 11%, fentanyl 4%, and sufentanil 0%. The decline of drug concentration over time was more pronounced for the more lipophilic drugs. CONCLUSIONS: Loss of highly lipophilic drugs in the extracorporeal membrane oxygenation circuits at 24 hours was remarkable. Drug loss is comparable with other hollow fiber extracorporeal membrane oxygenation systems but less than in silicone-based membranes especially in the first hours after injection.

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.
.

A study of the pharmacokinetics and thromboxane inhibitory activity of a single intramuscular dose of carprofen as a means to establish its potential use as an analgesic drug in white rhinoceros.

The alleviation of pain and prevention of suffering are key aspects of animal welfare. Unfortunately, analgesic drugs are not available for all species. White rhinoceros (Ceratotherium simum), representing one of such species, which survive poaching attempts inflicted with severe facial injuries and gunshot wounds, nonetheless require analgesic support. To improve treatment conditions, this study explored the use of carprofen for the treatment of pain and inflammation in white rhinoceros. The pharmacokinetics of 1 mg/kg intramuscular carprofen was evaluated in six healthy white rhinoceros. The half-life of λz and mean residence time was 105.71 ± 15.67 and 155.01 ± 22.46 hr, respectively. The area under the curve and the maximum carprofen concentration were 904.61 ± 110.78 µg ml-1  hr-1 and 5.77 ± 0.63 µg/ml, respectively. Plasma TXB2 inhibition demonstrated anti-inflammatory properties and indicated that carprofen may be effective for a minimum of 48 hr in most animals. With its long half-life further indicating that a single dose could be effective for several days, we suggest that carprofen may be a useful drug for the treatment of white rhinoceros.

Pharmacokinetics and bioavailability of tolfenamic acid in sheep.

The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC0-∞ ), elimination half-life (t1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.

PK/PD modeling of flunixin meglumine in a kaolin-induced inflammation model in piglets.

Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty-two piglets (6-8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand-held algometer was used to determine each piglet's mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut-off value of 24.5 newton). Serial venous blood samples were obtained to quantify flunixin in plasma using LC-MS/MS. A PKPD model describing the effect of flunixin on the mechanical nociceptive threshold was obtained based on an inhibitory indirect response model. A two-compartmental PK model was used. A significant effect of flunixin was observed for both doses compared to control group, with 4.4 mg/kg showing the most relevant (6-10 newton) and long-lasting effect (34 hr). The median IC50 was 6.78 and 2.63 mg/ml in groups MEDIUM and HIGH, respectively. The ED50 in this model was 6.6 mg/kg. Flunixin exhibited marked antinociceptive effect on kaolin-induced inflammatory hyperalgesia in piglets.