Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Pasteurella multocida in a tissue‐cage model in yellow cattle

The fluoroquinolone antimicrobial drug marbofloxacin was administered to yellow cattle intravenously and intramuscularly at a dose of 2 mg/kg of body weight in a two‐period crossover study. The pharmacokinetic properties of marbofloxacin in serum, inflamed tissue‐cage fluid (exudate), and noninflamed tissue‐cage fluid (transudate) were studied by using a tissue‐cage model. The in vitro and ex vivo activities of marbofloxacin in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 155.75, 153.00, and 138.88, respectively, after intravenous dosing and 160.50, 151.00, and 137.63, respectively, after intramuscular dosing. After intramuscular dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 21.13, 9.13, and 8.38, respectively. The ex vivo growth inhibition data after intramuscular dosing were fitted to the inhibitory sigmoid E_max equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.25, 31.29, and 109.62, and slightly lower values were obtained for transudate and exudate. It is proposed that these findings might be used with MIC₅₀ or MIC₉₀ data to provide a rational approach to the design of dosage schedules which optimize efficacy in respect of bacteriological as well as clinical cures.     

Pharmacokinetic/pharmacodynamic relationship of cefquinome against Pasteurella multocida in a tissue‐cage model in yellow cattle

The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1 mg/kg of body weight in a two‐period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue‐cage fluid (exudate), and noninflamed tissue‐cage fluid (transudate) were studied using a tissue‐cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. A concentration‐independent antimicrobial activity of cefquinome was confirmed for levels lower than 4 × MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (T > MIC) in serum was 14.10 h after intravenous and 14.46 h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P. multocida of MIC 0.04 μg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.     

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pelligand, L., King, J. N., Toutain, P. L., Elliott, J., Lees, P. Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation. J. vet. Pharmacol. Therap.  35 , 19–32. Robenacoxib is a novel nonsteroidal anti‐inflammatory drug developed for use in cats. It is a highly selective COX‐2 inhibitor. Results from previous feline studies showed that, despite a short half‐life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib’s pharmacokinetics and its ex vivo and in vivo selectivity for COX‐1 and COX‐2 using serum TxB₂ and exudate PGE₂ as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54–0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX‐1 in blood was transient, occurring only at high concentrations, but inhibition of COX‐2 in exudate persisted to 24 h. The potency ratio (IC₅₀ COX‐1: IC₅₀ COX‐2) was 171:1, and slopes of the concentration–effect relationship were 1.36 and 1.12 for COX‐1 and COX‐2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once‐daily administration.     

A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide‐induced diuresis in the dog

A pharmacokinetic/pharmacodynamic modelling approach was used to determine a dosage regimen which maximizes diuretic efficiency of torasemide in dogs. Kinetic profiles of plasma concentration, torasemide excretion rate in urine (TERU) and diuresis were investigated in 10 dogs after single oral administrations at 3 dose levels, 0.2, 0.8 and 1.6 mg/kg, and an intravenous injection of 0.2 mg/kg. Endogenous regulation was evidenced by a proteresis loop between TERU and diuresis. To describe the diuresis–time profile, TERU served as input into a turnover model with inhibition of loss of response, extended by a moderator acting on both loss and production of response. Estimated maximum inhibition of loss of response, I_max, was 0.984 showing that torasemide is an efficacious diuretic able to suppress almost total water reabsorption. A TERU_50, value producing half of I_max, of 1.45 μg/kg/h was estimated from the model. Pharmacokinetic and pharmacodynamic parameters were used to simulate the torasemide dose–effect relationship after oral administration. Model predictions were in good agreement with diuresis measured in a validation study conducted in 10 dogs, which were administered oral doses of 0.15, 0.4, 0.75, 1.5 and 4.5 mg/kg for 5 days. Finally, oral dose associated with the highest daily diuretic efficiency was predicted to be 0.1 mg/kg.     

Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats

This study describes the pharmacokinetics of intravenous hydromorphone in cats and the simultaneous measurement of antinociceptive pharmacodynamic effects using a thermal threshold testing system. Following establishment of a baseline thermal threshold, six adult cats were administered 0.1 mg/kg of hydromorphone intravenously. Thermal threshold testing and blood collection were conducted simultaneously at predetermined time points. Plasma hydromorphone concentrations were determined by a liquid chromatographic-mass spectral method and pharmacokinetic analysis was performed by nonlinear least squares regression analysis. Plasma hydromorphone concentrations declined rapidly over time, and were below the limit of quantification of the assay (LOQ = 1.0 ng/mL) by 360 min. In contrast, thermal thresholds rose from a pretreatment value of 40.9 +/- 0.65 degrees C (mean +/- SEM) to instrument cut-out (55 degrees C) within 15 min and remained significantly elevated from 15-450 min after treatment. Inspection of the data revealed no direct correlation between plasma hydromorphone concentrations and the antinociceptive effect of this drug in cats. These findings support the importance of conducting pharmacokinetic studies in parallel with objective measurements of drug effect.     

Pharmacokinetic/pharmacodynamic integration of cefquinome against Pasteurella Multocida in a piglet tissue cage model

To explore the in vivo antimicrobial activity of cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 10⁷ CFU/mL in a tissue cage, piglets received an intramuscular administration of cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of cefquinome, tissue cage fluid was collected for cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R² = 0.981) was the best PK/PD index that correlated with effectiveness of cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3‐log, 1/2‐log, and 1‐log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24‐hr treatment period. In conclusion, cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.     

Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant,a novel therapeutic for the pain and inflammation of osteoarthritis in dogs

A new anti‐inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9‐month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross‐over design with a 15‐day washout. Clinical observations were vomiting in one high‐dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUC_last values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9‐month safety study demonstrates that safety was evaluated at doses approximately 15‐fold above the demonstrated therapeutic dose of 2 mg/kg and 10‐fold over the ‘safety dose’, defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half‐tablets.     

Pharmacokinetic and pharmacodynamic evaluation of propofol administered to cats in a novel,aqueous, nano‐droplet formulation or as an oil‐in‐water macroemulsion1

This study evaluated pharmacokinetic and pharmacologic properties of a novel, non‐lipid microemulsion, 1% w/v formulation of propofol to a conventional macroemulsion formulation of propofol (Rapinovet^®) in cats. The study utilized a two‐period crossover design with two treatments and 10 female, intact, purpose bred domestic shorthair cats. Cats were fitted with telemetry transmitters for direct measurement of arterial blood pressure, pulse rate, electrocardiogram (ECG, lead II), and body temperature. At least 7 days separated treatments. Orotracheal intubation was the clinical endpoint utilized to evaluate adequate depth of anesthesia. Blood samples were drawn from jugular vascular access ports before propofol treatment; 3, 5, 15, 25, 35, 45, and 60 min and then 2, 3, 6, 8, 12, 18, and 24 h after administration of propofol into a cephalic vein. Whole blood samples were assayed for propofol concentrations using a gas chromatography/mass spectrometry method validated for feline blood at a limit of quantification of 5 ng/mL. Pulse rate, ECG, heart rhythm, respiratory rate, systolic, diastolic and mean arterial blood pressures, SpO₂, and body temperature were monitored continuously during each anesthetic episode. Time to lateral recumbency, orotracheal intubation, and extubation, time to sternal recumbency during recovery, times to adverse events, and doses of propofol required for induction to anesthesia were documented. Cats required 6.96 ± 0.90 mg propofol/kg from the novel microemulsion formulation of propofol and 7.07 ± 1.55 mg propofol/kg from Rapinovet^® to achieve anesthesia adequate to allow orotracheal intubation (P > 0.05). Areas under the dose‐normalized propofol concentration by time curves (AUC_0‐LOQ) and maximum propofol concentrations (C_max) were equal for the novel microemulsion formulation of propofol and Rapinovet^® (P > 0.05). Effects of anesthesia induction doses on cardiorespiratory values were comparable between treatments, and consistent with known effects of propofol anesthesia. Results provide evidence that the novel microemulsion formulation of propofol and Rapinovet^® macroemulsion produced comparable pharmacodynamic, physiological, and pharmacokinetic responses in cats. The unique composition of the microemulsion formulation, and the presence of an antimicrobial preservative minimize the potential for bacterial contamination and prolong shelf life.     

Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Aeromonas hydrophila in Chinese soft‐shelled turtles (Trionyx sinensis)

The single‐dose disposition kinetics of the antibiotic marbofloxacin were determined in Chinese soft‐shelled turtles (n = 10) after oral and intramuscular (i.m.) dose of 10 mg/kg bodyweight. The in vitro and ex vivo activities of marbofloxacin in serum against a pathogenic strain of Aeromonas hydrophila were determined. A concentration‐dependent antimicrobial activity of marbofloxacin was confirmed for levels lower than 4 × MIC. For in vivo PK data, values of AUC: minimum inhibitory concentration (MIC) ratio for serum were 1166.6 and 782.4 h, respectively, after i.m. and oral dosing of marbofloxacin against a pathogenic strain of A. hydrophila (MIC = 0.05 μg/mL). The ex vivo growth inhibition data after oral dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity and elimination of bacteria. The respective values were 23.79, 36.35 and 126.46 h. It is proposed that these findings might be used with MIC₅₀ or MIC₉₀ data to provide a rational approach to the design of dosage schedules, which optimize efficacy in respect of bacteriological as well as clinical cures.     

Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine

The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC(0-24)) and minimum inhibitory concentration (MIC), maximum plasma concentration (C(max)) and MIC and time during which plasma concentrations exceed the MIC have been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration-dependent where increasing concentrations at the locus of infection improve bacterial kill, or time-dependent where exceeding the MIC for a prolonged percentage of the inter-dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is 'bug and drug' specific, although ratios of 125 for AUC(0-24):MIC and 10 for C(max):MIC have been recommended to achieve high efficacy for concentration-dependent antimicrobial drugs, and exceeding MIC by 1-5 multiples for between 40 and 100% of the inter-dosing interval is appropriate for most time-dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration-dependent and beta-lactams, macrolides, lincosamides and glycopeptides are time-dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration-dependent antimicrobials by achieving an AUC(0-24):MIC ratio of greater than 100 or a C(max):MIC ratio of greater than 8. The relationships between time greater than MIC and resistance selection for time-dependent antimicrobials have not been well characterized.     

Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline‐free acid following subcutaneous administration in domestic goats

Pharmacokinetic (PK)–pharmacodynamic (PD) integration of crystalline ceftiofur‐free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high‐performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half‐life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time–kill curves for P. multocida demonstrated a time‐dependent killing action of drug. Considering target serum concentration of 0.20 μg/mL, PK‐PD values for AUC_24 h/MIC₉₀ and T > MIC₉₀, respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10–14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single‐dose administration. Based on MPC = 1.40 μg/mL for P. multocida, the PK‐PD indices, viz. T > MPC and AUC₂₄/MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida.     

Pharmacokinetic/pharmacodynamic assessments of 10 mg/kg tramadol intramuscular injection in yellow‐bellied slider turtles (Trachemys scripta scripta)

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. The aims of this study were to assess the pharmacokinetic/pharmacodynamic (PK/PD) properties of tramadol and its active metabolite M1 and to evaluate the effect of the renal portal system on the PK/PD parameters in yellow‐bellied slider turtles. Turtles (n = 19) were randomly assigned to four treatment groups, according to a masked, single‐dose, four‐treatment, unpaired, four‐period crossover design. Group A (n = 5) received a single i.m. dose of tramadol (50 mg/mL) at 10 mg/kg in the proximal hindlimb. Group B (n = 5) received the same i.m. dose but in the forelimb. Groups C (n = 5) and D (n = 4) received a single i.m. injection of saline (NaCl 0.9%) of equivalent volume to the volumes of tramadol injected in the hind‐ and forelimb, respectively. Groups were rotated (1‐month washout period) until the completion of the crossover study. Tramadol plasma concentrations were evaluated by a validated HPLC‐FL method. An infrared thermal stimulus was applied to the plantar surface of the turtles' hindlimbs to evaluate the thermal withdrawal latency (TWL). The two PK profiles of tramadol differed in the first 2 h following administration, but overlapped in the elimination phases. The metabolite M1 was formed in both the treatment groups, showing similar pharmacokinetic trends, although the amount of M1 was significantly higher (20%) in the hindlimb vs. forelimb group. Turtles given tramadol in the hind‐ and forelimb showed a significant increase in TWL over the periods of 0.5–48 and 8–48 h, respectively. The calculated % maximal possible response (% MPR) was low (about 24%). The PK/PD correlations between M1 plasma concentrations vs. % MPR appeared to show a counterclockwise hysteresis loop shape.     

Pharmacology of grapiprant,a novel EP4 antagonist: receptor binding,efficacy in a rodent postoperative pain model,and a dose estimation for controlling pain in dogs

Grapiprant is an analgesic and anti‐inflammatory drug in the piprant class that was approved in March 2016 by FDA's Center for Veterinary Medicine for the control of pain and inflammation associated with osteoarthritis (OA) in dogs. Grapiprant functions as a selective antagonist of the EP4 receptor, one of the four prostaglandin E₂ (PGE₂) receptor subtypes. The EP4 receptor mediates PGE₂‐elicited nociception, and grapiprant has been shown to decrease pain in several rat inflammatory pain models. It was also effective in reducing pain associated with OA in humans, providing evidence for its mechanism of action in these species. The estimated canine efficacy dose of between 1.3 and 1.7 mg/kg, p.o. with a methylcellulose suspension, once a day, was predicted based on calculations from comparative affinity of grapiprant to the dog, rat, and human EP4 receptors, serum protein binding, effective doses defined in rat models of pain and inflammation, and human clinical studies. The results of this study guided the doses to be tested in the pilot study and demonstrated the usefulness of the efficacy dose prediction method. The approved commercial tablet dose of grapiprant is 2 mg/kg once a day for the control of pain and inflammation associated with OA in dogs.     

药动/药效同步模型在兽用抗菌药物研究的应用概况

药动/药效同步模型是将药动学和药效学结合,用于研究药理效应随时间变化规律的一种模型。药动/药效同步模型在药理学和毒理学研究、临床应用及新药评价等领域得到越来越广泛的应用。随着抗菌药物的发展,耐药性问题日益成为全球关注的焦点。将药动/药效同步模型引入兽药研究中,不仅能够优化给药方案,避免细菌耐药性的产生,也能够为新药的开发提供研究基础。论文对兽用抗菌药物的分类、药动/药效同步模型的研究方法及其在国内外兽药研究中的应用现状进行综述,以期为药动/药效同步模型的兽医临床应用提供参考。     

Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration–time profiles obtained after intramuscular administration of Forcyl® in cattle. Animal's status, pre‐ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10 mg/kg as a single injection. The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC_0‐24 hr/MIC (area under the curve/minimum inhibitory concentration) greater than 125 hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved. The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1 μg/ml in pre‐ruminants and ruminants and 0.5 μg/ml in dairy cows.     

Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14C-benazeprilat and oral 14C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 approximately 1.0 h; Cl approximately 0.125 L/kg/h), elimination being principally biliary ( approximately 85%) rather than urinary ( approximately 15%). Nevertheless, inhibition of ACE was long-lasting (t1/2 16-23 h) due to high affinity binding of benazeprilat to ACE (Kd approximately 3.5 mmol/L, IC50 approximately 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).     

Pharmacokinetic behavior and pharmacokinetic/pharmacodynamic integration of marbofloxacin after subcutaneous administration in goats

The pharmacokinetic behavior of marbofloxacin was studied in goats after single-dose subcutaneous (SC) administration of 2mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography and the data obtained were subjected to non-compartmental kinetic analysis. Marbofloxacin peak plasma concentration (C(max)=1.77+/-0.24microg/mL) was reached 1.25+/-0.50h (T(max)) after SC administration. The elimination half-life (t(1/2beta)) and area under curve (AUC) were 5.74+/-1.21h and 8.15 vs 2.33microg h/mL, respectively. Taking into account the values obtained for the efficacy indices, it was concluded that a SC dose of 2mg/kg/24h of marbofloxacin could be adequate to treat infections caused by high susceptible bacteria like Escherichia coli or Salmonella spp.     

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.