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Month: June 2016

Development of a Novel Multi-compartment Granuloma Model to Predict Local Drug Distribution and Its Impact on Pharmacodynamics and Disease Progression in Tuberculosis

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Objectives: One of the hallmarks of pulmonary tuberculosis (TB) is the formation of granulomas, heterogeneous lesions composed of macrophage and neutrophil rich peripheral regions and a necrotic core, in the lungs of the infected host. Anti-TB drugs must penetrate these lesions to exert their effects. This work aimed to extend a permeability-limited lung model [1] … Continued

Diving into Best Practices for Pooling Clinical Trial Data

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If you’ve worked with a client drug development team approaching submission for approval, it’s likely you’ve heard discussions like this: Team member 1: “But, you can’t integrate the data from those studies because the treatment durations are different.”Team member 2: “That doesn’t matter, we still have to pool the results into a single integrated … Continued

Pharmacokinetics and Tissue Elimination of Funixin in Veal Calves

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OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves. ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old. PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after … Continued

Development of a Permeability-limited Model of the Human Brain and Cerebrospinal Fluid (CSF) to Integrate Known Physiological and Biological Knowledge: Estimating Time Varying CSF Drug Concentrations and Their Variability Using In Vitro Data

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A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and … Continued

Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Drug Interactions

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In vivo enzyme levels are governed by the rates of de novo enzyme synthesis and degradation. A current lack of consensus on values of the in vivo turnover half-lives of human cytochrome P450 (CYP) enzymes places a significant limitation on the accurate prediction of changes in drug concentration-time profiles associated with interactions involving enzyme induction … Continued

Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Healthy Adult Subjects Following Single and Multiple Ascending Doses

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The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were … Continued

Prediction of Drug-drug Interactions Arising From CYP3A Induction Using a Physiologically-based Dynamic Model

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Using physiologically-based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine … Continued

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