Dose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-abdominal Infections, Complicated Urinary Tract Infections, and Nosocomial Pneumonia
| Autor: | Paul Newell, Jianguo Li, Timothy J. Carrothers, David Melnick, Todd Riccobene, Gregory G. Stone, Wright W. Nichols, Shampa Das, Ian A. Critchley |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Avibactam Population Renal function Ceftazidime Microbial Sensitivity Tests 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Humans Pharmacology (medical) 030212 general & internal medicine education PK/PD models Pharmacology 0303 health sciences education.field_of_study 030306 microbiology business.industry Healthcare-Associated Pneumonia Ceftazidime/avibactam Anti-Bacterial Agents Drug Combinations Regimen Infectious Diseases chemistry Pharmacodynamics Urinary Tract Infections Intraabdominal Infections Minireview business Azabicyclo Compounds medicine.drug |
| Zdroj: | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY |
| Popis: | Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam MIC for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/liter for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CLCR) >50 ml/min across all approved indications and modified dosage regimens for patients with CLCR ≤50 ml/min. Subgroup simulations for individual phase 3 patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/liter achieved regardless of older age, obesity, augmented renal clearance, or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses. |
| Databáze: | OpenAIRE |
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