1846. Ceftolozane/Tazobactam Dose Evaluation for Pediatric Subjects with Complicated Intra-Abdominal Infection and Complicated Urinary Tract Infection
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD
  • Larson-1 IDWeek_90x42@200_printreadyR.pdf (906.9 kB)
  • 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 (13–59 d) and 4.1 kg (2.6–4.8 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.





    Kajal Larson, PhD1, Matthew G. Johnson, MPH1, Matthew L. Rizk, PhD1, Luzelena Caro, PhD2, John S. Bradley, MD, FIDSA, FPIDS, FAAP3, Jocelyn Ang, MD4 and Elizabeth Rhee, MD1, (1)Merck & Co. Inc., Kenilworth, NJ, (2)Merck & Co., Inc., Kenilworth, NJ, (3)Pediatric Infectious Diseases, University of California at San Diego School of Medicine, San Diego, CA, (4)Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, MI


    K. Larson, Merck: Employee , Salary

    M. G. Johnson, Merck: Employee , Salary

    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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