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Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

ABSTRACT: Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m² .

SUBMITTER: Franzese RC

PROVIDER: S-EPMC9298731 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT>MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT>1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT>MIC, 50%) of >0.9 for MICs of ?16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.).

Project description:The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations (fCss) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the fCss/MIC ratio for ceftazidime ≥4 (equivalent to 100% fT>4xMIC) and the fCss/CT ratio for avibactam >1 (equivalent to 100% fT >CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients (P = 0.023) or for pneumonia (P = 0.001) and less frequently for intra-abdominal infections and BSIs (P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not (P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.

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Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

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