S. Waxman

Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration

The pharmacokinetic behaviour of marbofloxacin, a new fluoroquinolone antimicrobial agent developed exclusively for veterinary use, was studied in mature horses (n = 5) after single-dose i.v. and i.m. administrations of 2 mg/kg bwt. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and data obtained were subjected to compartmental and noncompartmental kinetic analysis. This compound presents a relatively high volume of distribution (V(SS) = 1.17 +/- 0.18 l/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.19 +/- 0.042 l/kgh, which is related to a long elimination half-life (t(1/2beta) = 4.74 +/- 0.8 h and 5.47 +/- 1.33 h i.v. and i.m. respectively). Marbofloxacin was rapidly absorbed after i.m. administration (MAT = 33.8 +/- 14.2 min) and presented high bioavailability (F = 87.9 +/- 6.0%). Pharmacokinetic parameters are not significantly different between both routes of administration (P>0.05). After marbofloxacin i.m. administration, no adverse reactions at the site of injection were observed. Serum CK activity levels 12 h after administration increased over 8-fold (range 3-15) compared with pre-injection levels, but this activity decreased to 3-fold during the 24 h follow-up period. Based on the value of surrogate markers to predict clinical success, Cmax/MIC ratio or AUC/MIC ratio, single daily marbofloxacin dose of 2 mg/kg bwt may not be effective in treating infections in horses caused by pathogens with an MIC > or = 0.25 microg/ml. However, if we use a classical antimicrobial efficacy criteria, marbofloxacin can reach a high plasma peak concentration and maintain concentrations higher than MICs determined for marbofloxacin against most gram-negative veterinary pathogens throughout the administration period. Taking into account the fact that fluoroquinolones are considered to have a concentration-dependent effect and a long postantibiotic effect against gram-negative bacteria, a dose of 2 mg/kg bwt every 24 h could be adequate for marbofloxacin in horses.

Pharmacokinetics of a single intravenous dose of marbofloxacin in adult donkeys

Six donkeys each received 2 mg/kg marbofloxacin as a 10 per cent aqueous solution administered intravenously. Principal pharmacokinetic parameters were determined and two efficacy indices were computed by using pharmacokinetic parameters and selected mic90 values of marbofloxacin against pathogenic equine strains to predict the efficacy of the drug at this dose. The pharmacokinetics of marbofloxacin in donkeys was characterised by a large mean volume of distribution at a steady state (1·15 [0·09] l/kg) and a long mean (sd) elimination half-life of 9·24 (1·96) hours. It was also characterised by a relatively slow total body clearance of 0·10 (0·02) l/kg/hour, slower than in horses. Using mic90 values of marbofloxacin against pathogenic equine strains with a daily dose of 2 mg/kg, appropriate values of efficacy indicators were obtained only for Enterobacteriaceae. Daily intravenous doses of 0·33, 2·62 and 20 mg/kg were calculated for evaluation in clinical trials of infections due to Enterobacteriaceae, Staphylococcus aureus and Streptococci, respectively.

Pharmacokinetics of Marbofloxacin After Oral Administration to Eurasian Buzzards (Buteo buteo)

Abstract Marbofloxacin is a bactericidal fluoroquinolone developed exclusively for veterinary medicine. The pharmacokinetic disposition of this drug was studied after oral administration of a single dose (10 mg/kg) to 8 adult Eurasian buzzards (Buteo buteo). Plasma concentrations of marbofloxacin were measured during the 48-hour period after drug administration. A maximum plasma concentration of 3.70 μg/ml was achieved at 2.92 hours. Marbofloxacin was relatively slowly absorbed after oral administration (absorption half-life of 1.57 hours) and demonstrated a high bioavailability (92.15%). The elimination half-life was 9.48 hours, and the mean residence time was 10.65 hours. When using a minimum inhibitory concentration (MIC) breakpoint of 0.25 μg/ml, the calculated antimicrobial efficacy of orally administered marbofloxacin was higher than the range considered optimal for a dosing regimen against pathogens with an equivalent MIC. A dosage of 10 mg/kg administered once daily appears to be appropriate for the treatment of most infections with gram-negative bacteria that affect Eurasian buzzards.

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)) 4.20 +/- 1.66 microg x h/mL; C(max) 6.64 +/- 1.38 microg/mL; V(z) 4.80 +/- 0.91 L/kg; Cl(t) 2.64 +/- 0.84 L/h.kg; t((1/2)lambda) 1.35 +/- 0.40 h and MRT 1.50 +/- 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean +/- SD): C(max), 0.30 +/- 0.17 and 0.17 +/- 0.09 microg/mL; t(max), 1.75 +/- 0.76 and 0.69 +/- 0.30 h; t((1/2)lambda), 2.92 +/- 0.79 and 1.53 +/- 1.28 h and MRT, 5.10 +/- 1.12 and 2.56 +/- 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC(90) = 0.5 microg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.

Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose

The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51±0.22L and total plasma clearance (Cl) of 0.109±0.023L/hkg. The permanence of this drug was long in vultures (T(1/2)(λ)=12.51±2.52h; MRT(∞)=13.54±2.29h). The optimal dose of marbofloxacin estimated is 2.73mg/kg per day for the treatment of infections in vultures with MIC(90)=0.2μg/mL.

Marbofloxacin disposition after intravenous administration of a single dose in wild mallard ducks (Anas platyrhynchos).

Abstract Marbofloxacin, a fluoroquinolone developed specifically for veterinary use, has demonstrated considerable pharmokinetic variation among avian species. The goal of this study was to determine the disposition kinetics of marbofloxacin in mallard ducks (Anas platyrhynchos) after a single intravenous injection. Six wild mallard ducks were used in the study. Marbofloxacin was injected at a dose of 2 mg/kg into the basilic vein, and blood was subsequently collected at regular intervals from each bird. Plasma marbofloxacin concentrations were determined by using high-performance liquid chromatography. The volume of distribution at steady state was 1.78 ± 0.37 L/kg, and the total plasma clearance was 0.59 ± 0.08 L/kg per hour. Marbofloxacin had a relatively short permanence, with a elimination half-life of 2.81 ± 1.20 hours, a terminal half-life of 2.43 ± 0.61 hours, and a mean residence time of 2.99 ± 0.52 hour. The maximum observed concentration (Cmax) and area under the curve (AUC) were 1.34 ± 0.27 µg/mL and 3.75 ± 0.56 µg · h/mL, respectively. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax ∶ MIC value of 10 and an AUC ∶ MIC ratio of 125–250 associated with optimal bactericidal effects. By using the study data and MIC breakpoints of 0.125 µg/mL or 0.2 µg/mL, values derived for Cmax ∶ MIC were 9.37 ± 0.99 and 5.85 ± 0.62, respectively, and for AUC ∶ MIC were 29.99 ± 4.51 and 18.74 ± 2.82, respectively. By using MIC values of 0.125 and 0.2 µg/mL and a target AUC ∶ MIC  =  125, the calculated optimal daily marbofloxacin dosages for mallard ducks were 9.24 and 14.78 mg/kg, respectively. These results suggest that, primarily because of the high total plasma clearance observed, the marbofloxacin dose for treatment of bacterial diseases in mallard ducks should be increased after intravenous administration. Intravenous doses of 10–15 mg/kg should be assessed by studying their potential toxicity and efficacy in sick birds.

Pharmacokinetic and Pharmacodynamic Properties of Enrofloxacin in Southern Crested Caracaras (Caracara plancus)

Abstract: To determine the dosage of enrofloxacin in southern crested caracaras (Caracara plancus), plasma concentrations of enrofloxacin were measured by high-performance liquid chromatography after intravenous (IV) (5 mg/kg) and intramuscular (IM) (10 mg/kg) administration. This compound presented a relatively high volume of distribution (2.09 L/kg), a total body clearance of 0.24 L/kg·h, and a long permanence as shown by an elimination half-life of 7.81 hours after IV administration and a terminal half-life of 6.58 hours after IM administration. The areas under the concentration-time curves (AUC) were 21.92 and 34.38 μg·h/mL for IM and IV administration, respectively. Enrofloxacin was rapidly absorbed after IM administration with a time to reach maximum concentration of 0.72 hours and bioavailability of 78.76%. After IM administration, the peak drug concentration (Cmax) was 3.92 μg/mL. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax/MIC value of 10 and an AUC/MIC ratio of 125–250 associated with optimal bactericidal effects. By using the study data and a MIC breakpoint of 0.25 μg/mL, values of Cmax/MIC were 13.74 and 15.94 and for AUC/MIC were 90.73 and 139.63, for the IV and IM routes respectively. For the treatment of infectious diseases caused by microorganisms with MIC ≤0.25 μg/mL, the calculated optimal dosages were 7.5 and 9.5 mg/kg q24h by the IV and IM routes, respectively. For less susceptible bacteria, a dose increase should be evaluated. To treat caracara by the IV route against microorganisms with MIC ≤0.25 μg/mL, the dose should be higher than the 5 mg/kg used in our study, but possible side effects derived from an increase in the IV dose and efficacy in sick birds should be assessed.

PHARMACOKINETIC BEHAVIOR OF ENROFLOXACIN AND ITS METABOLITE CIPROFLOXACIN IN URUTU PIT VIPERS (BOTHROPS ALTERNATUS) AFTER INTRAMUSCULAR ADMINISTRATION

Abstract: Enrofloxacin is widely used in veterinary medicine and is an important alternative to treating bacterial infections, which play an important role as causes of disease and death in captive snakes. Its extralabel use in nontraditional species has been related to its excellent pharmacokinetic and antimicrobial characteristics. This can be demonstrated by its activity against gram-negative organisms implicated in serious infectious diseases of reptile species with a rapid and concentration-dependent bactericidal effect and a large volume of distribution. Pharmacokinetic parameters for enrofloxacin were investigated in seven urutu pit vipers (Bothrops alternatus), following intramuscular injections of 10 mg/kg. The plasma concentrations of enrofloxacin and its metabolite, ciprofloxacin, were measured using high-performance liquid chromatography. Blood samples were collected from the ventral coccygeal veins at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 108, and 168 hr. The kinetic behavior was characterized by a relatively slow absorption (time of maximal plasma concentration = 4.50 ± 3.45 hr) with peak plasma concentration of 4.81 ± 1.12 μg/ml. The long half-life during the terminal elimination phase (t1/2λ = 27.91 ± 7.55 hr) of enrofloxacin after intramuscular administration, calculated in the present study, could suggest that the antibiotic is eliminated relatively slowly and/or the presence of a slow absorption in urutu pit vipers. Ciprofloxacin reached a peak plasma concentration of 0.35 μg/ml at 13.45 hr, and the fraction of enrofloxacin metabolized to ciprofloxacin was 13.06%. If enrofloxacins minimum inhibitory concentration (MIC90) values of 0.5 μg/ml were used, the ratios AUCe+c : MIC90 (276 ± 67 hr) and Cmaxe+c : MIC90 (10 ± 2) reach the proposed threshold values (125 hr and 10, respectively) for optimized efficacy and minimized resistance development when treating infections caused by Pseudomonas. The administration of 10 mg/kg of enrofloxacin by the i.m. route should be considered to be a judicious choice in urutu pit vipers against infections caused by microorganisms with MIC values ≤0.5 μg/ml. For less susceptible bacteria, a dose increase and/or an interval reduction should be evaluated.