The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia^® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC_0–24 (after first and last doses), C_t (trough concentration—measured 24 h after each dose), C_max (after first and last doses), t_max (after first and last doses), λ_z (terminal disposition rate constant; after last dose), t_1/2 (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC_0–24 accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady‐state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant C_t values for each treatment group. Based on this model, 90% of steady‐state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.     

Inotropic and lusitropic effects of incremental doses of dobutamine in dogs with right ventricular apical pacing‐induced cardiac dysfunction

This study aimed to assess the effects of incremental doses of dobutamine on diastolic function in healthy and rapid ventricular apical pacing (RVAP)‐induced cardiac dysfunction anesthetized dogs. Inotropic and lusitropic effects of dobutamine (2, 4, 8, and 12 μg kg^?1 min^?1) were assessed through left ventricle (LV) pressure–volume relation and Doppler echocardiography in six female dogs before and after 8 weeks of RVAP. Peak rate of LV pressure fall (?dP/dt_min) improved with doses >4 μg kg^?1 min^?1 in healthy (4,490 ± 970 vs. 3,265 ± 471 mmHg/s, p < 0.05) and >8 μg kg^?1 min^?1 in RVAP dogs (3,385 ± 1,122 vs. 1,864 ± 849 mmHg/s, p < 0.05) while the time constant of relaxation (tau) reduced with doses >4 μg kg^?1 min^?1 in both groups (healthy: 24.0 ± 3.7 vs. 28.2 ± 4.9 ms; RVAP: 32.6 ± 8.5 vs. 37.5 ± 11.4 ms, p < 0.05) comparing with baseline. Indices of relaxation (?dP/dt_min and tau) suggested preserved lusitropic response in contrast with markedly reduced indices of contractility in the RVAP group compared with healthy group at same infusion rates. Doppler echocardiography showed significant reduction of elastic recoil in failing hearts. The results of this study demonstrated maximal positive lusitropic effects of dobutamine at a dose of 8 μg kg^?1 min^?1 in ventricular pacing‐induced cardiac dysfunction without further impairment of ventricular filling.     

Corneal innervation in mesocephalic and brachycephalic dogs and cats: assessment using in vivo confocal microscopy

Objective To determine the density of the canine and feline corneal neural network in healthy dogs and cats using in vivo confocal microscopy (IVCM). Animals examined A total of 16 adult dogs (9 Mesocephalic breeds, 7 Brachycephalic breeds) and 15 cats (9 Domestic Short-haired cats (DSH), 6 Persian cats) underwent IVCM. Procedure Animals were examined with a confocal corneal microscope (HRTII/RCM; Heidelberg Retina Tomograph II/Rostock Cornea Module^®, Heidelberg Engineering, Dossenheim, Germany). The investigations focused on the distribution of the corneal nerves and quantification of central subepithelial and subbasal nerve plexus. Results The corneal stromal nerve trunks, subepithelial and subbasal nerve plexus were observed. The nerve fiber density (NFD) quantified in nerve fiber length in mesocephalic dogs were 12.39 ± 5.25 mm/mm² in the subepithelial nerve plexus and 14.87 ± 3.08 mm/mm² in the subbasal nerve plexus. The NFD of the subepithelial nerve plexus in DSH cats was 15.49 ± 2.7 and 18.4 ± 3.84 mm/mm² in the subbasal nerve plexus. The subbasal NFD of DSH cats was significantly higher than in mesocephalic dogs (P = 0.037). The subepithelial NFD in brachycephalic dogs, and Persian cats were 10.34 ± 4.71 and 9.50 ± 2.3 mm/mm², respectively. The subbasal NFD measured 11.80 ± 3.73 mm/mm² in brachycephalic dogs, and 12.28 ± 4.3 mm/mm² NFD in Persian cats, respectively. The subepithelial and subbasal NFD in Persian cats were significantly lower than in DSH cats (P = 0.028, respectively, P = 0.031), in contrast to brachycephalic vs. mesocephalic dogs. Conclusion The noninvasive IVCM accurately detects corneal innervation and provides a reliable quantification of central corneal nerves.     

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T_1/2) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T_1/2 = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg⁻¹ min⁻¹) compared to maropitant (T_1/2 = 52.73 min ± 13.823 ml kg⁻¹ min⁻¹, CL = 178.57 ± 70.55) or morphine alone at higher doses (T_1/2 = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg⁻¹ min⁻¹). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.     

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 (AUC_0−∞), elimination half-life (t_1/2ʎz), total clearance (Cl_T) and volume of distribution at steady state (V_dss) 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 t_1/2ʎz, increased dose-normalized AUC_0-∞, and decreased Cl_T. 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.     

Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs

Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy‐induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8‐mg oral dose of ondansetron (Zofran^®) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography‐tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood‐ratio test. The peak plasma concentration (C_max) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half‐life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one‐compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1–13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.     

Comparison of the pharmacokinetic profiles of two different amphotericin B formulations in healthy dogs

This study was conducted to compare the pharmacokinetic profiles of conventional (Fungizone^®) and liposomal amphotericin B (AmBisome^®) formulations in order to predict their therapeutic properties, and evaluate their potential differences in veterinary treatment. For this purpose, twelve healthy mixed breed dogs received both drugs at a dose of 0.6 mg/kg by intravenous infusion over a 4‐min period in a total volume of 40 ml. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72 and 96 hr after dosing, and concentrations of drug in plasma were determined by high‐performance liquid chromatography (HPLC). Pharmacokinetics was described by a two‐compartment model. Although both formulations were administered at the same doses (0.6 mg/kg), the plasma pharmacokinetics of liposomal amphotericin B differed significantly from those of amphotericin B deoxycholate in healthy dogs (p < .05). Liposomal amphotericin B showed markedly higher peak plasma concentrations (approximately ninefold greater) and higher area under the plasma concentration curve values (approximately 14‐fold higher) compared to conventional formulation. It is concluded that AmBisome^® reached higher plasma concentration and lower distribution volume and had a longer half‐life compared to Fungizone^®, and therefore, AmBisome^® is reported to be an appropriate and effective choice for the treatment of systemic mycotic infections in dogs.     

Pharmocokinetic and pharmacodynamic evaluation of intravenous morphine in dogs

Morphine is considered the prototypical opiate analgesic. Despite the common use of morphine in dogs, ideal dosing strategies have not been formulated due to the difficulty in assessing its analgesic effects. The purpose of this study was to: 1) evaluate a noninvasive mechanical threshold device (von Frey device) to measure antinociceptive responses (pharmacodynamics) of opiates in dogs and 2) evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous (IV) morphine in dogs. Six healthy Beagle dogs were used. The von Frey threshold (vFT) response was evaluated hourly for 8 hours in each dog to examine the effect of repeated testing (controls). PK and PD (vFT) measurements were then made following a 1 mg kg^–1 IV bolus of morphine sulfate. A two way blinded crossover consisted of an 8 hour IV constant rate infusion of saline or morphine with hourly PD measurements. The individual CRI was based on individual PK data and adjusted every 2 hours to attain targeted plasma concentrations of morphine of 10, 20, 30, and 40 ng mL^–1. Blood samples were taken hourly in all phases, except the controls. No significant (p > 0.05) intraindividual changes in vFT occurred in the controls over 8 hours. The morphine bolus produced increased vFT at 1, 2, 3, and 4 hours post injection (p < 0.05). The E_MAX and EC₅₀ following the IV bolus were 213 ± 104% (increase from baseline) and 13.9 ± 5.8 ng mL^–1, respectively. The CRI produced increased vFT at plasma concentrations >30 ng mL^–1, when compared to saline controls (p < 0.05). Targeted plasma concentrations were inconsistent at higher infusion rates, suggesting the PK of morphine may change during CRI. The actual mean ± SD CRI plasma concentrations (ng ml^–1) were 10.8 ± 3.0, 22.7 ± 7.4, 32.4 ± 13.9, 35.7 ± 16.9. Morphine dosing protocols should be re‐evaluated, as sufficient analgesia may not be obtained from published dosages. Intravenous boluses may be more predictable than CRI.     

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

The pharmacokinetics of afoxolaner and milbemycin oxime (A3 and A4 forms) in dogs were evaluated following the oral administration of NexGard Spectra ^® (Merial), a fixed combination chewable formulation of these two active pharmaceutical ingredients. Absorption of actives was rapid at levels that provide the minimum effective doses of 2.5 mg/kg and 0.5 mg/kg of afoxolaner and milbemycin oxime, respectively. The time to maximum afoxolaner plasma concentrations (t_max) was 2–4 h. The milbemycin t_max was 1–2 h. The terminal plasma half‐life (t_1/2) and the oral bioavailability were 14 ± 3 days and 88.3% for afoxolaner, 1.6 ± 0.4 days and 80.5% for milbemycin oxime A3 and 3.3 ± 1.4 days and 65.1% for milbemycin oxime A4. The volume of distribution (V_d) and systemic clearance (Cls) were determined following an IV dose of afoxolaner or milbemycin oxime. The V_d was 2.6 ± 0.6, 2.7 ± 0.4 and 2.6 ± 0.6 L/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The Cls was 5.0 ± 1.2, 75 ± 22 and 41 ± 12 mL/h/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The pharmacokinetic profile for the combination of afoxolaner and milbemycin oxime supports the rapid onset and a sustained efficacy for afoxolaner against ectoparasites and the known endoparasitic activity of milbemycin oxime.     

Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos)

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross‐over design with a washout period between doses. Mean (±SD) C_max following IM injection was 1.6 (±0.8) µg/ml with T_max at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (V_D) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min^?1 kg^?1. Elimination half‐lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.     

Pharmacokinetics of an injectable long‐acting parenteral formulation of doxycycline hyclate in pigs

Based on its ideal PK/PD ratios, doxycycline hyclate (DOX‐h), a time‐dependant antibacterial, is ideally expected to achieve sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer‐based matrix was used to produce a 10% long‐acting injectable preparation (DOX‐h‐LA) and its serum concentrations vs. time profile investigated after its injection to pigs in the pericaudal s.c. by parallel design. Results were compared with the forced oral bolus dose and i.v. pharmacokinetics of DOX‐h. For this study, 12 recently weaned pigs per group were included in this trial, and a dose of 20 mg/kg was injected in all cases. DOX‐h‐LA showed the greatest values for bioavailability (115.38%); maximum serum concentration (Cmax) value was 1.5 ± 0.2 with a time to reach Cmax of 3.41 ± 0.04 h and an elimination rate constant of 70.93 ± 0.87 h. Considering minimum effective serum concentration of 0.5 μg/mL, a dose interval of at least 5 days can be achieved for DOX‐h‐LA, whereas p.o. and i.v. dosing of DOX‐h may only last 11 and 15 h, respectively. Pigs were slaughtered on day 30 after this trial, and no visible remnants of the preparation were detected neither fibrosis was observed after a thorough macroscopic and histopathological analysis.     

Pharmacokinetics,metabolism and excretion of celecoxib,a selective cyclooxygenase‐2 inhibitor,in horses

Celecoxib, a nonsteroidal anti‐inflammatory drug, is frequently used to treat arthritis in humans with minimal gastrointestinal side effect compared to traditional NSAIDs. The primary aim of this study was to determine the pharmacokinetic profile of celecoxib—a selective cyclooxygenase‐2 (COX‐2) inhibitor in horses. Six horses were administered a single oral dose of celecoxib at 2 mg/kg (body weight). After oral dosing, the drug reached a maximum concentration (mean ± SD) in blood of 1,088 ± 324 ng/ml in 4.58 hr. The elimination half‐life was 13.60 ± 3.18 hr, and the area under the curve was 24,142 ± 1,096 ng hr ml^?1. The metabolism of celecoxib in horses was via a single oxidative pathway in which the methyl group of celecoxib is oxidized to a hydroxymethyl metabolite and is further oxidized to form a carboxylic acid metabolite. Celecoxib is eliminated mainly through faeces as unchanged drug and as metabolites in urine. Therefore, instructions for a detection time following therapeutic dosing of celecoxib can be set by the racing practitioner and veterinarians to control illegal use in horse racing based on the results of this study.     

Pharmacokinetics studies of enrofloxacin injectable in situ forming gel in dogs

The objective of this study was to evaluate the pharmacokinetic characteristics of enrofloxacin (ENR) injectable in situ gel we developed in dogs following a single intramuscular (i.m.) administration. Twelve healthy dogs were randomly divided into two groups (six dogs per group), then administrated a single 20 mg/kg body weight (b.w.) ENR injectable in situ gel and a single 5 mg/kg b.w. ENR conventional injection, respectively. High‐performance liquid chromatography (HPLC) was used to determine ENR plasma concentrations. The pharmacokinetic parameters of ENR injectable in situ gel and conventional injection in dogs are as follows: MRT (mean residence time) (45.59 ± 14.05) h verse (11.40 ± 1.64) h, AUC (area under the blood concentration vs. time curve) (28.66 ± 15.41) μg·h/mL verse (11.06 ± 3.90) μg·h/mL, c_max (maximal concentration) (1.59 ± 0.35) μg/mL verse (1.46 ± 0.07) μg/mL, t_max (time needed to reach c_max) (1.25 ± 1.37) h verse (1.40 ± 0.55) h, t_1/2λz (terminal elimination half‐life) (40.27 ± 17.79) h verse (10.32 ± 0.97) h. The results demonstrated that the in situ forming gel system could increase dosing interval of ENR and thus reduced dosing frequency during long‐term treatment. Therefore, the ENR injectable in situ gel seems to be worth popularizing in veterinary clinical application.     

Predictive equations of maintenance energy requirement for healthy and chronically ill adult dogs

Maintenance energy requirement (MER) is the energy amount necessary for dogs to maintain their weight and body condition. Some factors can influence the MER, such as gender, age, neutering status and also diseases. The present retrospective study aimed to evaluate MER of adult dogs with several diseases and compare with the MER of healthy adult dogs, observing the influence of parameters such as body condition score (BCS), neutering status, gender, age, diagnosis and type of food on MER of these dogs. A total of 165 adult dogs with weight changes of ≤5% were included and divided in groups according to diagnosis. Mean MER for healthy dogs was 86.09 kcal/BW^0.75, which differed from NRC and FEDIAF recommendations for inactive adult dogs (p = .047). Lowest MERs were of the endocrinopathies (78.52 ± 19.32 kcal/BW^0.75), orthopaedic diseases (59.71 ± 19.30 kcal/BW^0.75) and neurologic diseases (78.83 ± 32.66 kcal/BW^0.75) groups. Gastrointestinal diseases (99.59 ± 20.36 kcal/BW^0.75), orthopaedic diseases (59.71 ± 19.30 kcal/BW^0.75) and neoplasia (95.61 ± 21.02 kcal/BW^0.75) groups were the only groups that differed from the mean MER of healthy adult dogs. Regarding BCS, for each increasing point in a 9-point scale, there was a decrease of 9.8 kcal/BW^0.75 on MER, independent of diagnosis (p < .0001; r² = .55). There was no difference regarding breed size gender and age, but neutered dogs presented lower MER (p = .031). Based on data obtained from the present study, it can be concluded that it is necessary to consider BCS, age, neutering status and diagnosis when calculating MER, both in healthy dogs and chronically ill dogs.     

Pharmacokinetics and dynamics of mycophenolate mofetil after single‐dose oral administration in juvenile dachshunds

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young‐aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose‐bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole‐blood mitogen‐stimulated T‐cell proliferation was determined using a flow cytometric assay. Plasma MPA C_max (mean ± SD, 9.33 ± 7.04 μg/ml) occurred at <1 hr. The AUC_0–∞ (mean ± SD, 12.84±6.62 hr*μg/ml), MRT_inf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.     

Total antioxidant capacity and protein peroxidation intensity in seminal plasma of infertile and fertile dogs

The aim of this study was to evaluate the total antioxidant capacity and protein peroxidation intensity in seminal plasma of infertile and fertile dogs. The study was conducted on 10 infertile and 10 fertile dogs of various breeds. Infertility was defined as conception failure at least three matings with different bitches. Semen was collected by manual manipulation. The sperm concentration and motility parameters were evaluated using CASA Hamilton Thorne, Vers. IVOS 12.3. The morphology of spermatozoa and the percentage of live and dead sperm cells were assessed microscopically, total antioxidant capacity and the content of SH‐groups in seminal plasma were determined spectrophotometrically, the contents of protein peroxidation markers in seminal plasma, bityrosine and formylokinurenine, were determined using spectrofluorimetric methods. Sperm concentration and total sperm count were significantly (p < 0.05) lower in infertile dogs than in fertile dogs (99.92 ± 3 0.05 × 10⁶/ml vs. 282.07 ± 48.27 × 10⁶/ml; 214.19 ± 114.74 × 10⁶ vs. 747.57 ± 210.94 × 10⁶, respectively). The percentage of spermatozoa with normal morphology and the most determined motility parameters differed significantly (p < 0.05) between both groups. The mean values of total antioxidant capacity in the seminal plasma were significantly (p < 0.05) lower (19.95 ± 20.94 vs. 25.66 ± 23.18 µmol/g protein), whereas the mean contents of bityrosine and formylokinurenine in seminal plasma were significantly (p < 0.05) higher in infertile dogs than in fertile dogs (3.71 ± 4.83 µg/mg protein vs. 1.55 ± 2.00 µg/mg protein and 0.37 ± 0.45 µg/mg protein vs. 0.14 ± 0.08 µg/mg protein, respectively). In conclusion, the obtained results suggest that the poor semen quality and infertility in dogs could be associated with lowered total antioxidant capacity and increased protein peroxidation in seminal plasma as a consequence of oxidative stress.     

The pharmacokinetics of cytarabine administered at three distinct subcutaneous dosing protocols in dogs with meningoencephalomyelitis of unknown origin

The objective of this study was to evaluate the pharmacokinetics of the standard cytarabine (Ara‐C) protocol (50 mg/m² subcutaneously every 12 hr for 2 days) used for dogs with neuroinflammatory disease and compare it to two more practical protocols (a single 200 mg/m² subcutaneous dose and two 100 mg/m² subcutaneous doses every 12 hr). Four client‐owned dogs previously diagnosed with meningoencephalomyelitis of unknown origin were administered three distinct Ara‐C protocols with a 21‐day washout between each protocol. A complete blood count was performed seven days after each dosing protocol to assess for clinically relevant myelosuppression. No adverse events were observed. Plasma Ara‐C concentrations were measured using a validated liquid chromatography coupled to tandem mass spectrometry assay. The mean maximal concentrations in this study were 4,230, 9,293, and 16,675 ng/ml for a single dose of 50, 100, and 200 mg/m², respectively. There was a linear relationship between dose and drug exposure. Drug exposure was similar regardless of the dosing protocol when the total dose was analyzed, with an area under the concentration versus time curve of 37,026, 38,465, and 32,510 ng × hr/ml for 50, 100, and 200 mg/m², respectively.     

Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis

Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant‐bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 ± 37 μg/mL at 15 min. The systemic clearance was 347 ± 117 mL/h/kg, and the steady‐state volume of distribution was 223 ± 67 mL/kg. Dialysis clearance was 71.1 ± 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 ± 0.150. The half‐life (T_1/2) in dogs with IHD decreased compared with those without IHD, and the reduction in T_1/2 was greater in renal failure patients than in normal patients. Sixty‐nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.     

Oral and intravenous l‐[1‐13C]phenylalanine delivery measure similar rates of elimination when gastric emptying and splanchnic extraction are accounted for in adult mixed hounds1–4

There are few reported estimates of amino acid (AA) kinetics in adult mammals and none exist in adult dogs. The study objectives were to evaluate the use of oral isotope delivery in contrast to the more commonly used intravenous (IV) delivery to estimate AA kinetics in adult dogs and to estimate splanchnic extraction and gastric emptying using a commonly accepted mathematical model. Dogs received 25 × 1/2‐hourly meals (13 g/kg BW/day) and either an oral or IV bolus of l‐ [1‐¹³C]Phe (12 mg/kg BW). Blood samples were taken immediately before each feeding. Concentrations of plasma Phe were measured using liquid chromatography‐tandem mass spectrometry. There were no differences in baseline plasma Phe concentrations (34 μm ± 0.61), Phe distribution volume, Phe pool size and rate constants between dogs when the tracer was administered IV or orally (p > 0.25). Decay curve for plasma l ‐[1‐¹³C]Phe differed between IV and oral dosing protocols with IV dosing fit best using a two‐compartment model. Phe disappeared from plasma at a mean rate of 2.8%/min. Estimates of gastric emptying and splanchnic extraction did not differ based on oral or IV tracer dosing when the decay curves were fit with the two‐compartment model (p > 0.40). The half‐life for gastric emptying was 18 min, and first‐pass Phe extraction by the splanchnic bed was 24% of the dietary Phe. These results suggest that oral isotope dosing can be used as an alternative to IV isotope dosing in studies that utilize a primed, constant dosing approach to measure protein and amino acid kinetics.     

Pharmacokinetic indices for cefovecin after single‐dose administration to adult sea otters (Enhydra lutris)

Seven sea otters received a single subcutaneous dose of cefovecin at 8 mg/kg body weight. Plasma samples were collected at predetermined time points and assayed for total cefovecin concentrations using ultra‐performance liquid chromatography and tandem mass spectrometry. The mean (±SD) noncompartmental pharmacokinetic indices were as follows: C_Max (obs) 70.6 ± 14.6 μg/mL, T_{Max (obs)} 2.9 ± 1.5 h, elimination rate constant (k_el) 0.017 ± 0.002/h, elimination half‐life (t_1/2kel) 41.6 ± 4.7 h, area under the plasma concentration‐vs.‐time curve to last sample (AUC_last) 3438.7 ± 437.7 h·μg/mL and AUC extrapolated to infinity (AUC_0→∞) 3447.8 ± 439.0 h·μg/mL. The minimum inhibitory concentrations (MIC) for select isolates were determined and used to suggest possible dosing intervals of 10 days, 5 days, and 2.5 days for gram‐positive, gram‐negative, and Vibrio parahaemolyticus bacterial species, respectively. This study found a single subcutaneous dose of cefovecin sodium in sea otters to be clinically safe and a viable option for long‐acting antimicrobial therapy.