Pharmacokinetic evaluation of marbofloxacin after intravenous administration at different ages in llama crias, and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation

Abstract

In llama crias (tekes), Escherichia coli and Staphylococcus aureus are major pathogens, and marbofloxacin could be a suitable choice. The objectives of this study were (a) to evaluate the serum pharmacokinetics of marbofloxacin (5 mg/kg) after intravenous administration in tekes and simulate a multidose regimen; (b) to emulate pharmacokinetic profiles after single dose and steady-state conditions by Monte Carlo simulation (c) to determine the MIC of regional strains of Escherichia coli and Staphylococcus aureus; (d) to perform a PK/PD analysis by Monte Carlo simulation. Pharmacokinetics of marbofloxacin was evaluated in six animals at 3, 10, 24, 50, and 80 days after birth. Marbofloxacin were determined by HPLC. A steady-state multi-dose simulation was carried out, and concentration-time profiles were generated by Monte Carlo simulation. MIC of marbofloxacin against regional E. coli and S. aureus strains were also determined. Finally, a PK/PD analysis was conducted by Monte Carlo simulation. After pharmacokinetic analysis, clearance showed a trend to increase (0.14 and 0.18 L kg hr ), and AUC (36.74 and 15.21 μg hr ml ) and Vss (3.06 and 3.37 L/kg) trended to decrease at 3 and 80 days-old, respectively, showing accumulation ~50% in animals with 3 days. All strains tested of E. coli (MIC = 0.06 μg/ml) and S. aureus (MIC = 0.25 μg/ml) were susceptible to marbofloxacin. PK/PD analysis suggests that the therapeutic regimen of marbofloxacin could be effective for infections caused by E. coli strains in animals between 3 and 80 days, with a CFR for C /MIC > 10 of 100% and for AUC /MIC > 125 of 99.99%; and for infections produced by S. aureus in animals between 3 and 24 days old, with a CFR for C /MIC > 10 of 93.08% and for AUC /MIC > 60 of 97.01%, but a higher dose should be used in older animals, because PK/PD endpoints were not met.

A Literature Review of Selected Bacterial Diseases in Alpacas and Llamas—Epidemiology, Clinical Signs and Diagnostics

“…In addition, they recommend administering balanced isotonic crystalloid fluids IV or performing a plasma transfusion. Rubio-Langre et al [ 80 ] showed that marbofloxacin is effective against E. coli infections in llama crias between 3 and 80 days of age at a dose of 5 mg/kg IV.…”

Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach

“…Considering this, MC simulation could be a most useful approach in identification of ALB concentrations significance for inter‐individual MPA pharmacokinetic variability. 25 , 26 , 27 …”

“…Considering this, MC simulation could be a most useful approach in identification of ALB concentrations significance for inter-individual MPA pharmacokinetic variability. [25][26][27] The aim was the identification of mathematical correlation and association between both, total and unbound MPA concentration in relation to ALB, BM, age and eGFR in stable kidney transplant recipients. Furthermore, investigation was conducted with the aim to clarify the role of C SAL MPA in adverse effects profile.…”

“…Mathematical approach can help in establishing the link between total plasma (C P ), C SAL of MPA and various factors that influence C P ‐C SAL relationship, such as ALB. Considering this, MC simulation could be a most useful approach in identification of ALB concentrations significance for inter‐individual MPA pharmacokinetic variability 25–27 …”

Effect of supportive therapy on the pharmacokinetics of intravenous marbofloxacin in endotoxemic sheep

“…The antibacterial effect of fluoroquinolones is concentration‐dependent, and peak plasma concentration ( C max )/minimum inhibitory concentration (MIC) and area under the concentration–time curve (AUC 0–24 )/MIC ratios are used to evaluate their efficiencies. For maximum efficacy and minimal resistance in marbofloxacin treatment, the C max /MIC ratio is expected to be ≥10 for bacteria and AUC 0–24 /MIC ratio is expected to be ≥125 for gram‐negative bacteria and ≥60 for gram‐positive bacteria such as S. aureus (Lees, Concordet, Aliabadi, & Toutain, 2006; McKellar, Sanchez Bruni, & Jones, 2004; Rubio‐Langre et al, 2018; Toutain & Lees, 2004). In order to determine AUC 0–24 /MIC and C max /MIC, the pharmacokinetics (PKs) and pharmacodynamics (PDs) of marbofloxacin and the target species need to be specified.…”