Background: Ceftolozane/tazobactam (TOL/TAZ), a novel antipseudomonal cephalosporin/β-lactamase inhibitor combination antibiotic approved in adults for treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), has a potentially important role in the treatment of pediatric infections. In adult cIAI/cUTI patients, TOL/TAZ is administered as a 1.5 g (1 g TOL/ 0.5 g TAZ) intravenous (IV) infusion over 1 h q8h. Data for subjects 3 mo to <18 yr from an ongoing Phase 1 pharmacokinetic (PK) and safety study of TOL/TAZ in pediatric subjects have been presented previously. Here, we present preliminary data for neonatal subjects. Further, a population PK (pop PK) approach to estimate optimal doses for treatment of cIAI and cUTI in pediatric subjects (birth to 18 yr) are presented.
Methods: Neonatal subjects (birth [>32 wk gestation to 7 d postnatal] to <3 mo of age) received a single IV dose of 20/10 mg/kg TOL/TAZ. Plasma PK data from this group, older pediatric age cohorts, and 12 adult Phase 1 and 2 studies were used to develop pop PK models for TOL/TAZ; simulations were performed to identify safe and efficacious pediatric doses based on adult exposures and PK/PD targets.
Results: Seven neonatal subjects received TOL/TAZ. Mean (range) age and weight were 39.5 d (1359 d) and 4.1 kg (2.64.8 kg), respectively. All PK-evaluable subjects (n=6) met the PK/PD efficacy targets. The mean (SD) AUC0-∞ of TOL was 171 (46.5) μg∙h/mL and the mean (SD) AUClast of TAZ was 22.5 (8.16) μg∙h/mL. One subject experienced multiple adverse events unrelated to study drug.
For the pop PK analysis, two-compartment models described TOL/TAZ data well. Based on simulations in pediatric patients with eGFR >50 mL/min/1.73 m2, doses of 1.5g (12 to <18 yr) and 20/10 mg/kg (birth to <12 yr) given via 1-h IV infusion provide exposures that achieve probability of target attainment ≥90% based on time above a MIC of 4 μg/mL (30% for TOL, Fig. 1) and threshold concentration of 1 μg/mL (20% for TAZ, Fig. 2).
Conclusion: In an ongoing pediatric PK study, TOL/TAZ was well tolerated in subjects from birth to 3 mo of age. Population PK models developed for TOL/TAZ characterized the PK of pediatric subjects (birth to 18 yr) well and were suitable to select TOL/TAZ doses for evaluation in pediatric cIAI and cUTI studies.
M. L. Rizk, Merck: Employee , Salary
L. Caro, Merck: Employee , Salary
J. S. Bradley, None
J. Ang, Merck: Investigator , Site Principal Investigator for Merck- Sponsored clinical trials
E. Rhee, Merck: Employee , Salary
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