J. vet. Pharmacol. Therap. 2017;1–12. wileyonlinelibrary.com/journal/jvp | 1 © 2017 John Wiley & Sons Ltd Received: 12 September 2016 | Accepted: 22 March 2017 DOI: 10.1111/jvp.12409 ORIGINAL ARTICLE Pharmacokinetics, milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin, after intravenous and intramuscular administration to lactating goats A. M. Lorenzutti 1 | N. J. Litterio 1 | M. A. Himelfarb 1 | M. d. P. Zarazaga 1 | M. I. San Andrés 2 | J. J. De Lucas 2 1 Facultad de Ciencias Agropecuarias-Unidad Asociada al CONICET, Universidad Católica de Córdoba, Córdoba, Argentina 2 Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain Correspondence Dr. Augusto Matías Lorenzutti, Universidad Católica de Córdoba-Unidad Asociada al CONICET, Córdoba, Argentina. Email: matiaslorenzutti@hotmail.com The main objectives of this study were (i) to evaluate the serum pharmacokinetic be- haviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regi- men on steady-state conditions, (ii) to determine the minimum inhibitory concentra- tion (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady-state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emer- gence of resistance. The study was carried out with six healthy, female, adult Anglo Nubian lactating goats. Marbofloxacin was administered at 5 mg/kg bw by IV and IM route. Serum and milk concentrations of MFX were determined with HPLC/uv. From 106 regional strains of CNS isolated from caprine mastitis in herds from Córdoba, Argentina, MICs and MPCs were determined. MIC 90 and MPC 90 were 0.4 and 6.4 μg/ ml, respectively. MIC and MPC-based PK/PD analysis by Monte Carlo simulation indi- cates that IV and IM administration of MFX in lactating goats may not be adequate to recommend it as an empirical therapy against CNS, because the most exigent end- points were not reached. Moreover, this dose regimen could increase the probability of selecting mutants and resulting in emergence of resistance. Based on the results of Monte Carlo simulation, the optimal dose of MFX to achieve an adequate antimicro- bial efficacy should be 10 mg/kg, but it is important take into account that fluoroqui- nolones are substrates of efflux pumps, and this fact may determine that assumption of linear pharmacokinetics at high doses of MFX may be incorrect. 1 | INTRODUCTION Marbofloxacin (MFX) is a third generation fluoroquinolone developed exclusively for veterinary use and exerts a bactericidal concentration- dependent antimicrobial effect. It is indicated for the treatment of urinary, respiratory and digestive infections, pyoderma, otitis, soft tis- sue and reproductive tract infections (such endometritis, pyometra or mastitis) (EMEA, 2000; Meunier, Acar, Martel, Kroemer, & Valle, 2004; USP, 2007). Pharmacokinetics of MFX was studied after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration in adult nonpregnant goats (Waxman et al., 2001; Waxman-Dova et al., 2007) and lactating goats by IV and SC administration at a dose of 2 mg/kg bw (Fernández-Palacios, 2013). Moreover, IV pharmacoki- netics of MFX was studied in febrile goats and kids (Waxman et al., 2003, 2004), and a pharmacokinetic/pharmacodynamic (PK/PD) modelling of MFX was performed by Sidhu, Landoni, Ali-Abadi, and Lees (2010).