Evaluation of enrofloxacin use in koalas (Phascolarctos cinereus) via population pharmacokinetics andMonteCarlo simulation

Abstract

Clinically normal koalas (n = 6) received a single dose of intravenous enrofloxacin (10 mg/kg). Serial plasma samples were collected over 24 h, and enrofloxacin concentrations were determined via high-performance liquid chromatography. Population pharmacokinetic modeling was performed in S-ADAPT. The probability of target attainment (PTA) was predicted via Monte Carlo simulations (MCS) using relevant target values (30-300) based on the unbound area under the curve over 24 h divided by the minimum inhibitory concentration (MIC) (fAUC0-24 /MIC), and published subcutaneous data were incorporated (Griffith et al., 2010). A two-compartment disposition model with allometrically scaled clearances (exponent: 0.75) and volumes of distribution (exponent: 1.0) adequately described the disposition of enrofloxacin. For 5.4 kg koalas (average weight), point estimates for total clearance (SE%) were 2.58 L/h (15%), central volume of distribution 0.249 L (14%), and peripheral volume 2.77 L (20%). MCS using a target fAUC0-24 /MIC of 40 predicted highest treatable MICs of 0.0625 mg/L for intravenous dosing and 0.0313 mg/L for subcutaneous dosing of 10 mg/kg enrofloxacin every 24 h. Thus, the frequently used dosage of 10 mg/kg enrofloxacin every 24 h subcutaneously may be appropriate against gram-positive bacteria with MICs ≤ 0.03 mg/L (PTA > 90%), but appears inadequate against gram-negative bacteria and Chlamydiae in koalas.

Review of some pharmacokinetic and pharmacodynamic properties of anti‐infective medicines administered to the koala (Phascolarctos cinereus)

“…Determination of the PK profile of a single enrofloxacin i.v. bolus of 10 mg/kg was also subsequently undertaken (Black, Landersdorfer, et al., ). These studies reported the following results:…”

“… Low oral bioavailability of both enrofloxacin and marbofloxacin : Oral enrofloxacin administration at 20 mg/kg resulted in a median (range) maximal plasma concentration ( C max ) of 0.94 (0.76–1.0) μg/ml (Griffith et al., ) which was similar to the C max when a smaller dose rate of 5 mg/kg was administered orally to dogs with a C max mean ± SD of 1.24 ± 0.39 μg/ml (Bidgood & Papich, ). As clearance was determined at approximately 8 ml min −1 kg −1 in the koala (Black, Landersdorfer, et al., ) vs. a mean ± SD of 13.33 ± 1.14 ml min −1 kg −1 in the dog (Bidgood & Papich, ), demonstrating similar enrofloxacin clearance between species, the oral absorption of enrofloxacin appears lower in the koala than in the dog, as most of the oral plasma concentration vs. time data points in koalas were below the lower level of assay quantification [LLOQ]) of 0.40 μg/ml. Likewise marbofloxacin appeared to exhibit poor oral absorption; when administered at 10 mg/kg, once daily, p.o., plasma concentrations were below the LLOQ of 0.48 μg/ml (Griffith et al., ); whereas 5 mg/kg p.o.…”

“…Comparing s.c. and i.v. AUC data (Black, Landersdorfer, et al., ; Griffith, ), enrofloxacin has an s.c. bioavailability of approximately 35% in the koala; however, s.c. bioavailability is reported as 77% in rabbits (Broome, Brooks, Babish, Copeland, & Conzelman, ) and >90% in alpacas (Rae‐Gandolf, Papich, Bringardner, & Atkinson, ). The reason for the disparity in enrofloxacin SC bioavailability between the koala and the other species has not been elucidated. Minimal ciprofloxacin concentrations: Ciprofloxacin is an active metabolite of enrofloxacin in many species, with both enrofloxacin and ciprofloxacin responsible for antimicrobial activity in vivo (Lautzenhiser, Fialkowski, Bjorling, & Rosin, ).…”

“…to dogs, the C max of ciprofloxacin mean (± SD ) was 0.36 ± 0.10 μg/ml, 3.00 ± 1.41 hr after administration (Bidgood & Papich, ), whereas a 10 mg/kg i.v. enrofloxacin bolus administered to six koalas resulted in maximal ciprofloxacin concentrations of 0.13–0.25 μg/ml in the plasma of half of the koalas at 2 min but was below LLOQ (0.13 μg/ml) at 15 min (Black, Landersdorfer, et al., ). Likewise Griffith et al.…”

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

“…This approach is widely used in human medicine (DeRyke, Kuti, & Nicolau, ; Frei, Wiederhold, & Burgess, ; Roberts, Kirkpatrick, & Lipman, ; Tanigawara, Nozawa, & Tsuda, ; Turnidge & Paterson, ; Zelenitsky, Ariano, Harding, & Forrest, ). A growing interest in population pharmacokinetics and MCS applied to the assessment of anti‐infectives dosage regimens was recently shown in veterinary medicine (Black, Landersdorfer, Bulitta, Griffith, & Govendir, ; Rey et al., ; Vilalta, Giboin, Schneider, El Garch, & Fraile, ; Yuan et al., ).…”