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.

The Brain Exposure Efficiency (BEE) Score.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented. BEE addresses the need to incorporate the role of trans-BBB influx and efflux active transporters by considering key brain penetrance parameters, namely, steady state unbound brain to plasma ratio of drug (Kp,uu) and dose normalized unbound concentration of drug in brain (Cu,b). BEE was devised using quantitative structure-activity relationships (QSARs) and molecular modeling studies on known transporter proteins and their ligands. The developed algorithms are provided as a user-friendly open source calculator to assist in optimizing a brain penetrance strategy during the early phases of small molecule molecular therapeutic design.

A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery.

The separation of the brain from blood by the blood-brain barrier and the bloodcerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting the central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrate that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS penetration. Indeed, CCSF usually over-estimates Cu-brain for efflux substrates and it provides no additional value over Cu-plasma as the surrogate of Cu-brain for highly permeable non-efflux substrates. A strategy described here for the evaluation of CNS penetration is to use in vitro permeability, P-glycoprotein (Pgp) and breast cancer resistance protein efflux assays and Cu-brain/Cu-plasma in preclinical species. Cu-plasma should be used as the surrogate of Cu-brain for highly permeable non-efflux substrates with no evidence of impaired distribution into the brain. When drug penetration into the brain is impaired, we recommend using (total brain concentration * unbound fraction in the brain) as Cu-brain in preclinical species or Cu-plasma/in vitro Pgp efflux ratio if Pgp is the major limiting mechanism for brain penetration.