Population Pharmacokinetic Modeling of Free Plasma and Free Brain Concentrations of Ceftaroline in Healthy and Methicillin-Resistant Staphylococcus aureus-Infected Wistar Rats.

A population pharmacokinetic model was developed to describe alterations in ceftaroline brain disposition caused by meningitis in healthy and methicillin-resistant Staphylococcus aureus (MRSA)-infected rats. Blood and brain microdialysate samples were obtained after a single bolus dose of ceftaroline fosamil (20 mg/kg) administered intravenously. Plasma data were modeled as one compartment, and brain data were added to the model as a second compartment, with bidirectional drug transport between plasma and brain (Qin and Qout). The cardiac output (CO) of the animals showed a significant correlation with the relative recovery (RR) of plasma microdialysis probes, with animals with greater CO presenting lower RR values. The Qin was approximately 60% higher in infected animals, leading to greater brain exposure to ceftaroline. Ceftaroline brain penetration was influenced by MRSA infection, increasing from 17% (Qin/Qout) in healthy animals to 27% in infected animals. Simulations of a 2-h intravenous infusion of 50 mg/kg every 8 h achieved >90% probability of target attainment (PTA) in plasma and brain for the modal MRSA MIC (0.25 mg/L), suggesting that the drug should be considered an option for treating central nervous system infections.

Development and validation of an LC-MS/MS method to quantify ceftaroline in microdialysate samples from plasma and brain: Application to a preclinical pharmacokinetic investigation.

A bioanalytical LC-MS/MS method was developed and validated to determine ceftaroline in microdialysate samples from plasma and brain. Ceftaroline was separated using a C18 column and a mobile phase consisting of water and acetonitrile, both with 5 mM of ammonium formate and acid formic 0.1%, eluted as gradient. Ceftaroline was monitored using electrospray ionization operating on positive mode (ESI+) monitoring the transition 604.89 > 209.3 m/z. The method showed linearity in the concentration range of 0.5-500 ng/mL for brain microdialysate and 0.5-2500 ng/mL for plasma microdialysate with coefficients of determination ≥0.997. The inter-and intra-day precision, the accuracy, and the stability of the drug in different conditions were in accordance with the acceptable limits determined by international guidelines. Plasma pharmacokinetics and brain distribution of the drug were carried out after intravenous administration of 20 mg/kg of ceftaroline to male Wistar rats. The estimated geometric mean (geometric coefficient of variation) area under the curve (AUC0-∞) was 4.68 (45.8%) mg·h/L and 1.20 (54.2%) mg·h/L for plasma and brain, respectively, resulting in a brain exposure of about 33% (AUCfree brain/AUCfree plasma). The results indicate that ceftaroline presents good penetration in the brain when considering free plasma and free brain concentrations.

The effect of breed, sex, and drug concentration on the pharmacokinetic profile of ivermectin in cattle.

Ivermectin (IVM) is one of the most widely used antiparasitic drugs worldwide and has become the drug of choice for anthelmintic and tick treatment in beef cattle production. It is known that pharmacokinetic parameters are fundamental to the rational use of a drug and food safety and these parameters are influenced by different factors. The aim of this study was to evaluate the pharmacokinetic profile of IVM in Bos indicus, Bos taurus, and crossbreed cattle (B. indicus × B. taurus) kept under same field conditions and the possible impacts of sex and IVM formulation (1% and 3.15%). It was observed that IVM concentration was significantly affected by breed. The plasma concentrations of IVM, AUC, Cmax , and t1/2ß were significantly higher in B. indicus compared to B. taurus. Crossbreed animals showed an intermediate profile between European and Indian cattle. No alteration in pharmacokinetics parameters was detected when comparing different gender. Concerning the pharmacokinetic data of IVM formulation, it was verified that Tmax , AUC, and t1/2ß were higher in 3.15% IVM animals than those from 1% IVM formulation. The results clearly indicated that the IVM plasma concentrations in B. indicus were higher than that in B. taurus.