Pharmacokinetics and pharmacodynamics of cefovecin in dogs

A series of in vivo, ex vivo and in vitro studies were conducted to determine the pharmacokinetic and pharmacodynamic properties of cefovecin, a new injectable cephalosporin, in dogs. Absolute bioavailability was determined in a two-phase cross-over study in dogs receiving 8 mg/kg bodyweight (b.w.) of cefovecin by either subcutaneous (s.c.) or intravenous (i.v.) route. After s.c. administration, cefovecin was fully bioavailable (100%), the mean maximum plasma concentration (Cmax) was 121 microg/mL and the mean apparent elimination half-life (t1/2) was 133 h. Clearance was measured to be 0.76 mL/h/kg after i.v. dosing. The concentration of cefovecin in urine measured 14 days after s.c. administration was 2.9 microg/mL. Plasma protein binding was determined by equilibrium dialysis; over concentrations ranging from 10 to 100 microg/mL (i.e. up to the approximate Cmax following an 8 mg/kg dose), protein binding of 98.7% to 96.0% was observed, however, binding was lower at higher concentrations. Total and free concentrations of cefovecin were determined in plasma, transudate and exudate collected from dogs previously implanted subcutaneously with tissue cages. Mean peak concentrations of free cefovecin were almost three times higher in transudate than in plasma and remained above 0.25 microg/mL for 19 days. The ex vivo antibacterial killing activity (vs. Staphylococcus intermedius, MIC 0.25 microg/mL) was measured in serum, transudate and exudate collected from dogs which had received 8 mg/kg b.w. of cefovecin subcutaneously. Transudate exhibited higher antimicrobial killing activity than serum. Activity in serum and exudate exhibited a mean reduction in bacterial counts of S. intermedius of at least three log units up to 72 h postadministration. Bactericidal activity (>3 log10 reduction of bacterial counts) was observed in transudate up to 12 days postadministration. The slow elimination and long lasting ex vivo antibacterial killing activity following administration of cefovecin are desirable pharmacokinetic and pharmacodynamic attributes for an antimicrobial drug with 14-day dosing intervals.     

Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs

Protamine zinc insulins are generally considered to be long acting, with slow absorption from subcutaneous tissue. Protamine zinc recombinant human insulin (PZIR) may be useful to treat diabetic dogs. The purpose of this study was to describe the pharmacokinetics and pharmacodynamics of PZIR in dogs. PZIR was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design, at doses of 0.3 or 0.5 U/kg (each n=5), 0.8 U/kg (n=10), or 0.8 U/kg at three separate sites (n=6). Insulin and glucose concentrations were measured over 24 h. The shapes of insulin and glucose curves were variable among dogs, and the relationship between insulin dose, concentration, and glucose-lowering effect was nonlinear. For single-site 0.8 U/kg, median (range) onset of action was 3.5 h (0.5-10 h), time to glucose nadir was 14 h (5 to >24 h), and duration of action was >24 h (16 to >24 h). Mathematical model predictions of times to 50% and 90% insulin absorption, and fraction of insulin absorbed in 24 h, were not significantly different among protocols. Results confirm the tendency toward a late onset and long duration of action for PZIR in dogs. This insulin may be an alternative treatment option for diabetic dogs.     

Pharmacokinetics and pharmacodynamics of guanidine hydrochloride in an hereditary myasthenia gravis-like disorder in dogs

The pharmacokinetic parameters of guanidine hydrochloride were analysed in dogs with an hereditary neuromuscular transmission disorder by the use of 14C-guanidine hydrochloride. The content of intravenously administrated 14C-guanidine hydrochloride in plasma, urine and faeces was determined by liquid scintillation counting. The drug was rapidly distributed in the organism with a plasma half-life of 7-8 h and most was eliminated in the urine. The clinical and electrophysiological effects of guanidine hydrochloride on the muscular weakness and fatigue induced by exercise were determined after oral and intravenous administration. Guanidine hydrochloride improved muscle-function, but had no apparent effect when administered during an attack of weakness. An effective level of guanidine in plasma (2-10 micrograms/ml) changed the muscle response evoked by trains of repetitive stimulation. The myasthenic decrement during short stimulation trains was unchanged.     

Pharmacokinetics and pharmacodynamics of oral acetaminophen in combination with codeine in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600 mg (14.4–23.1 mg/kg) and codeine phosphate at 90 mg (2.1–3.3 mg/kg) equivalent to 67.5 mg codeine base (1.6–2.5 mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine‐6‐glucuronide were 7.95 μg/mL, 11.0 ng/mL, and 3819 ng/mL, respectively. Morphine concentrations were <1 ng/mL. The terminal half‐lives of acetaminophen, codeine, and codeine‐6‐glucuronide were 0.94, 1.71, and 3.12 h. There were no significant changes in vF thresholds, except at 12 h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12 h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs.     

Pharmacokinetics and ex‐vivo pharmacodynamics of cefquinome against Klebsiella pneumonia in healthy dogs

A two‐period cross‐over study was carried to investigate the pharmacokinetics (PK) and ex‐vivo pharmacodynamics (PD) of cefquinome when administrated intravenously (IV) and intramuscularly (IM) in seven healthy dogs at a dose of 2 mg/kg of body weight. Serum concentrations were determined by HPLC‐MS/MS assay and cefquinome concentration vs. time data after IV and IM were best fit to a two‐compartment open model. Cefquinome mean values of area under concentration–time curve (AUC) were 5.15 μg·h/mL for IV dose and 4.59 μg·h/mL for IM dose. Distribution half‐lives and elimination half‐lives after IV dose and IM dose were 0.27 and 0.44 h, 1.53 and 1.94 h, respectively. Values of total body clearance (Cl_B) and volume of distribution at steady‐state (V_ss) were 0.49 L·kg/h and 0.81 L/kg, respectively. After IM dose, C_max was 2.53 μg/mL and the bioavailability was 89.13%. For PD profile, the determined MIC and MBC values against K. pneumonia were 0.030 and 0.060 μg/mL in MHB and 0.032 and 0.064 μg/mL in serum. The ex vivo time‐kill curves also were established in serum. In conjunction with the data on MIC, MBC values and the ex vivo bactericidal activity in serum, the present results allowed prediction that a single cefquinome dosage of 2 mg/kg may be effective in dogs against K. pneumonia infection.     

Pharmacokinetics and pharmacodynamics in the newborn

Pharmacokinetics and pharmacodynamics in the newborn are multifaceted: maturation processes of the systems committed to absorption, distribution, metabolism, and excretion partially overlap, making the newborn an extremely dynamic system, especially if compared with adults. In this short note, some of the relevant variables able to regulate these processes are reviewed according to published literature data.

     

Pharmacokinetics and pharmacodynamics in the newborn

Pharmacokinetics and pharmacodynamics in the newborn are multifaceted: maturation processes of the systems committed to absorption, distribution, metabolism, and excretion partially overlap, making the newborn an extremely dynamic system, especially if compared with adults. In this short note, some of the relevant variables able to regulate these processes are reviewed according to published literature data.     

Pharmacokinetics and pharmacodynamics of morphine in llamas

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of morphine in llamas. ANIMALS: 6 healthy adult llamas. PROCEDURES: Llamas received morphine sulfate in a randomized crossover design. In phase 1, they received IV or IM administration of morphine at 0.05 or 0.5 mg/kg, respectively; in phase 2, they received IV administration of morphine at 0.05, 0.25, or 0.5 mg/kg. Plasma morphine and morphine-6-glucuronide concentrations were determined by validated methods. Body temperature, heart rate, respiratory rate, sedation, and analgesia were assessed and compared with plasma concentrations by regression analysis. RESULTS: Total body clearance was similar between IV administration of morphine sulfate at 0.25 and 0.5 mg/kg (mean +/- SD, 25.3 +/- 6.9 mL/min/kg and 27.3 +/- 5.9 mL/min/kg, respectively), and linearity was demonstrated between these doses. Bioavailability of morphine following IM administration at 0.5 mg/kg was 120 +/- 30%. Body temperature and sedation increased as the dose of morphine administered increased. Heart rate was unaffected by varying doses. Respiratory rate decreased as dose increased. Analgesia was difficult to assess as a result of high individual variability. Intravenous administration of morphine at 0.25 mg/kg provided the most consistent increase in tolerance to electric stimulation. Pharmacodynamic modeling revealed a sigmoidal relationship between plasma concentration and sedation score. CONCLUSIONS AND CLINICAL RELEVANCE: Morphine was characterized by a large apparent volume of distribution and high systemic clearance in llamas. A prolonged half-life was observed with IM injection. Intravenous administration of morphine sulfate at 0.25 mg/kg every 4 hours is suggested for further study.     

Pharmacokinetics and pharmacodynamics of meloxicam in piglets

The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16–23 days old) were studied using a stratified parallel group design. One group ( n  = 13) received 0.4 mg/kg meloxicam intravenously, while the other group ( n  = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E₂ (PGE₂) concentration, but the inhibition of PGE₂ in the meloxicam group was limited. The inhibition of thromboxane B₂ (TXB₂) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE₂ inhibition in exudate.     

Pharmacokinetics of gemcitabine and its primary metabolite in dogs after intravenous bolus dosing and its in vitro pharmacodynamics

Gemcitabine is a chemotherapeutic agent used to treat a variety of cancers in humans and dogs. In this study, the plasma pharmacokinetics of gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), were investigated in dogs after intravenous bolus gemcitabine doses of 3, 10, and 30 mg/kg. Furthermore, the intracellular accumulation of the active metabolite gemcitabine triphosphate, as a surrogate pharmacodynamic endpoint, was also determined in vitro in canine melanoma cells. Gemcitabine was characterized by linear kinetics, while dFdU dose proportionality remains unknown. The average gemcitabine clearance was 0.560 L/h.kg and volume of distribution at steady-state of 1.27 L/kg. The average terminal elimination half-life, depending on dose, ranged from 1.75 to 3.23 h. Plasma concentrations of dFdU peaked at approximately 2 h post-dosing. In vitro intracellular gemcitabine triphosphate accumulation was saturated with increasing extracellular gemcitabine concentrations. These data can be used to rationally design gemcitabine dosage regimes for canine oncology patients and as a basis for future investigations on the in vivo intracellular accumulation of gemcitabine triphosphate in dogs.     

Pharmacokinetics and pharmacodynamics of clemastine in healthy horses

Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 microg/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 microg/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations.     

Pharmacokinetics and pharmacodynamics of terbutaline in healthy horses

OBJECTIVE: To determine pharmacokinetics of terbutaline in healthy horses and to relate serum terbutaline concentrations with the drug's pharmacodynamic effects. ANIMALS: 6 healthy horses. PROCEDURE: Horses were given terbutaline i.v. (10 microg/kg of body weight) and, 1 week later, p.o. (100 microg/kg). Responses to drug administration (eg, heart rate and serum lactate concentration) were measured. Serum terbutaline concentration was measured by means of gas chromatography with mass spectrometry. Protein binding was determined in vitro. RESULTS: Following i.v. administration, median maximum serum terbutaline concentration and mean residence time were 9.3 ng/ml and 30 minutes, respectively. Bioavailability following oral administration was < 1%. All horses developed sweating, trembling, excitement, and tachycardia during i.v. infusion. The 2 horses with the highest serum terbutaline concentrations developed severe tachycardia and CNS stimulation; 30 minutes after the i.v. infusion was completed, they were hyperventilating and lethargic. Heart rate and serum lactate concentration increased as serum terbutaline concentration increased. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that terbutaline is rapidly cleared from the bloodstream following i.v. administration to horses, suggesting that continuous i.v. infusion would be needed to maintain therapeutic serum concentrations. Oral administration of terbutaline to horses is not practical because of the low bioavailability.     

Pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid in horses

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid (EACA), including the effects of EACA on coagulation and fibrinolysis in healthy horses. ANIMALS: 6 adult horses. PROCEDURES: Each horse received 3.5 mg of EACA/kg/min for 20 minutes, i.v. Plasma EACA concentration was measured before (time 0), during, and after infusion. Coagulation variables and plasma alpha(2)-antiplasmin activity were evaluated at time 0 and 4 hours after infusion; viscoelastic properties of clot formation were assessed at time 0 and 0.5, 1, and 4 hours after infusion. Plasma concentration versus time data were evaluated by use of a pharmacokinetic analysis computer program. RESULTS: Drug disposition was best described by a 2-compartment model with a rapid distribution phase, an elimination half-life of 2.3 hours, and mean residence time of 2.5 +/- 0.5 hours. Peak plasma EACA concentration was 462.9 +/- 70.1 microg/mL; after the end of the infusion, EACA concentration remained greater than the proposed therapeutic concentration (130 microg/mL) for 1 hour. Compared with findings at 0 minutes, EACA administration resulted in no significant change in plasma alpha(2)-antiplasmin activity at 1 or 4 hours after infusion. Thirty minutes after infusion, platelet function was significantly different from that at time 0 and 1 and 4 hours after infusion. The continuous rate infusion that would maintain proposed therapeutic plasma concentrations of EACA was predicted (ie, 3.5 mg/kg/min for 15 minutes, then 0.25 mg/kg/min). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that EACA has potential clinical use in horses for which improved clot maintenance is desired.     

Pharmacokinetics and pharmacodynamics of dermorphin in the horse

Dermorphin is a μ‐opioid receptor‐binding peptide that causes both central and peripheral effects following intravenous administration to rats, dogs, and humans and has been identified in postrace horse samples. Ten horses were intravenously and/or intramuscularly administered dermorphin (9.3 ± 1.0 μg/kg), and plasma concentration vs. time data were evaluated using compartmental and noncompartmental analyses. Data from intravenous administrations fit a 2‐compartment model best with distribution and elimination half‐lives (harmonic mean ± pseudo SD) of 0.09 ± 0.02 and 0.76 ± 0.22 h, respectively. Data from intramuscular administrations fit a noncompartmental model best with a terminal elimination half‐life of 0.68 ± 0.24 (h). Bioavailability following intramuscular administration was variable (47–100%, n = 3). The percentage of dermorphin excreted in urine was 5.0 (3.7–10.6) %. Excitation accompanied by an increased heart rate followed intravenous administration only and subsided after 5 min. A plot of the mean change in heart rate vs. the plasma concentration of dermorphin fit a hyperbolic equation (simple Emax model), and an EC₅₀ of 21.1 ± 8.8 ng/mL was calculated. Dermorphin was detected in plasma for 12 h and in urine for 48 or 72 h following intravenous or intramuscular administration, respectively.     

Pharmacokinetics and pharmacodynamics of antiulcer agents in llama

Plasma concentration time curves following intravenous (i.v.) administration of 1.5 mg/kg of ranitidine, 0.2 mg/kg, 0.4 mg/kg and 0.8 mg/kg of omeprazole, respectively, were analysed in six llamas. Plasma profiles after i.v. administration of both drugs showed plasma concentrations declining in a biexponential manner with a rapid distribution phase. Pharmacokinetics parameters after ranitidine administration to six llamas showed a mean elimination half-life of 1.53 +/- 0.26 h. The mean volume of distribution (Vdss) in llamas was 1.77 +/- 0.31 L/kg, and mean body clearance in llamas was 0.778 +/- 0.109 L/kg/h. Ranitidine produced only a small transitory (<1 h) decline in acid production when administered i.v. at a dose of 1.5 mg/kg. Omeprazole showed dose-dependent nonlinear pharmacokinetics. The mean half-life of 0.2 mg/kg i.v. omeprazole was shorter than that of 0.4 and 0.8 mg/kg i.v. omeprazole, i.e. 0.61, 0.72 and 1.07 h, respectively. The area under the curve (AUC) and mean residence time (MRT) increased with increasing dose, while clearance decreased as dose increased. The decline in acid production following 0.2 mg/kg i.v. omeprazole was highly variable and did not produce a clinically useful suppression of third compartment acid production. In contrast, both 0.4 mg/kg and 0.8 mg/kg omeprazole i.v. administration significantly reduced third compartment acid production. The reduction in acid production following 0.8 mg/kg omeprazole was not significantly greater than the reduction observed following 0.4 mg/kg dosage. Misoprostol (10 microg/kg) was administered i.v. in an absolute alcohol solution. Two animals collapsed following drug administration. While the side-effects could have been produced by either misoprostol or the alcohol vehicle, the clinical changes were more consistent with an adverse drug reaction. Unfortunately, the limitation of UV detection did not provide the sensitivity needed to quantify the amount of misoprostol in llama plasma, and the pharmacokinetics could not be evaluated.     

Pharmacokinetics and pharmacodynamics of tilmicosin in sheep and cattle

Tilmicosin is a long-acting macrolide antibiotic currently approved for treatment of bovine respiratory disease in the USA. Serum pharmacokinetics of tilmicosin were compared between cattle (major species) and sheep (minor species) after subcutaneous injection in order to evaluate a new potential application of the drug in currently nonapproved species. There were no significant differences in the elimination rates, maximum serum concentrations, half-lives ( t _1/2), areas under the curve ( AUC ), areas under the first-moment curve ( AUMC ), and mean residence times. Volume of distribution ( V d_area) and clearance ( Cl ), when normalized by body weight, were also similar. The only significantly different parameter was time at which maximum drug concentration was reached ( t _max), with sheep having the t _max of 3.9 h, compared to 0.5 h in cattle.
  Although macrolides are considered to be one of the safest anti-infective drugs, adverse cardiovascular effects of several macrolides have been reported. The cardiopulmonary effects of tilmicosin were monitored in healthy adult sheep after receiving a single subcutaneous (s.c.) injection of tilmicosin at the dose of 10 mg/kg, and no significant changes were found. The study indicates that tilmicosin can be used safely and effectively in sheep at the given dose, with no adverse cardiopulmonary effects.     

Pharmacokinetics, pharmacodynamics, and analgesic effects of morphine after rectal, intramuscular, and intravenous administration in dogs

OBJECTIVE: To compare systemic bioavailability and duration for therapeutic plasma concentrations and cardiovascular, respiratory, and analgesic effects of morphine administered per rectum, compared with IV and IM administration in dogs. ANIMALS: 6 healthy Beagles. PROCEDURE: In a randomized study, each dog received the following: morphine IV (0.5 mg/kg of body weight), morphine per rectum (1, 2, and 5 mg/kg as a suppository and 2 mg/kg as a solution), and a control treatment. Intramuscular administration of morphine (1 mg/kg) was evaluated separately. Heart and respiratory rates, systolic, diastolic, and mean blood pressures, adverse effects, and plasma morphine concentrations were measured. Analgesia was defined as an increase in response threshold, compared with baseline values, to applications of noxious mechanical (pressure) and thermal (heat) stimuli. Data were evaluated, using Friedman repeated-measures ANOVA on ranks and Student-Newman-Keuls post-hoc t-tests. RESULTS: Significant differences were not found in cardiovascular, respiratory, or analgesia values between control and morphine groups. Overall systemic bioavailability of morphine administered per rectum was 19.6%. Plasma morphine concentration after administration of the highest dose (5 mg/kg) as a suppository was significantly higher than concentrations 60 and 360 minutes after IV and IM administration, respectively. A single route of administration did not consistently fulfill our criteria for providing analgesia. CONCLUSIONS AND CLINICAL RELEVANCE: Rectal administration of morphine did not increase bioavailability above that reported for oral administration of morphine in dogs. Low bioavailability and plasma concentrations limit the clinical usefulness of morphine administered per rectum in dogs.