Pharmacokinetics of enrofloxacin HCl-2H₂O (Enro-C) in dogs and pharmacokinetic/pharmacodynamic Monte Carlo simulations againstLeptospiraspp.

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) ratios of reference enrofloxacin (Enro-R) and enrofloxacin as HCl-2H2O (Enro-C), as well as Monte Carlo simulations based on composite MIC50 and MIC90 (MIC, minimum inhibitory concentration) vs. Leptospira spp., were carried out in dogs after their intramuscular (IM) or oral administration (10 mg/kg). Plasma determination of enrofloxacin was achieved by means of high-performance liquid chromatography. Maximum plasma concentration values after oral administration were 1.47 ± 0.19 µg/mL and 5.3 ± 0.84 µg/mL for Enro-R and Enro-C, respectively, and 1.6 ± 0.12 µg/mL and 7.6 ± 0.93 µg/mL, respectively, after IM administration. Areas under the plasma vs. time concentration curve in 24 h (AUC0–24) were 8.02 µg/mL/h and 36.2 µg/mL/h for Enro-Roral and Enro-Coral, respectively, and 8.55 ± 0.85 µg/mL/h and 56.4 ± 6.21 µg/mL/h after IM administration of Enro-R and Enro-C, respectively. The PK/PD ratios and Monte Carlo simulations obtained with Enro-C, not Enro-R, indicated that its IM administration to dogs will result in therapeutic concentrations appropriate for treating leptospirosis. This is the first time enrofloxacin has been recommended to treat this disease in dogs.

Outpatient Clinical Trial in Dogs With Leptospirosis Treated With Enrofloxacin Hydrochloride-Dihydrate (ENRO-C)

“…Fluoroquinolone drugs show a concentration-dependent activity and the C MAX /MIC ≥ 10 ratio is critical to optimize its effectiveness (41). The apparently favorable pharmacokinetics of enro-C in dogs (13), and its almost 100% efficacy in bacteriological cure in an experimental model of hamster leptospirosis (42), prompted the use of enro-C in this trial. The chosen dose of enro-C at 10 mg/kg/day IM, followed by oral administration, was based on achieving the aforementioned ratio through previous Monte-Carlo simulations for dogs (13).…”

“…The apparently favorable pharmacokinetics of enro-C in dogs (13), and its almost 100% efficacy in bacteriological cure in an experimental model of hamster leptospirosis (42), prompted the use of enro-C in this trial. The chosen dose of enro-C at 10 mg/kg/day IM, followed by oral administration, was based on achieving the aforementioned ratio through previous Monte-Carlo simulations for dogs (13). Such simulations applied to pharmacokinetics reduce uncertainty, when using a given dose in a clinical scenario and allow a therapeutic prognosis if the referred C MAX /MIC ≥ 10 target is reached.…”

“…In its technical manuals, the pioneer brand of enrofloxacin, does not mention its possible use to treat canine leptospirosis 1 , nor was this fluoroquinolone considered as an option in the consensus statement published by experts (5). In contrast, favorable pharmacokinetics (PK) of a recrystallized form of enrofloxacin such as HCl-2H 2 O (enro-C) in dogs, its pharmacokinetic/pharmacodynamic ratios (PK/PD) and Monte-Carlo simulations, indicate that its IM administration may result in concentrations that may be appropriate for the treatment of leptospirosis (13). These data were the motivation to carry out this outpatient clinical trial with dogs affected by leptospirosis and treated with enro-C.…”

Oral Plus Topical Administration of Enrofloxacin-Hydrochloride-Dihydrate for the Treatment of Unresponsive Canine Pyoderma. A Clinical Trial

“…This study was not designed to find bacterial patterns of antibiotic resistance, but a complete bacteriological work should follow, as it can help explain why enro-C was able to achieve the great successes observed in the UDCP cases. From a pharmacological point of view, the exceptionally high values of C MAX and AUC 0-24 obtained by enro-C in dogs [27] might be part of the explanation. Additionally, the concurrent oral administration of enro-C plus its topical application as a gel in the affected areas can achieve particularly high concentrations of enrofloxacin in the affected skin, a proposal that also needs validation through experimental work.…”

“…A new recrystallized form of enrofloxacin, defined as hydrochloride-dihydrate (enro-C), has been characterized [25,26]. Enro-C shows considerably higher water solubility than the original compound, and it shows higher bioavailability than that of the original drug in dogs [27]. The C MAX value after oral administration of enro-C was approximately three times higher compared to the enrofloxacin reference preparation.…”