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Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.
J Clin Pharmacol. 2016 Jan; 56(1):56-66.JC

Abstract

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Authors+Show Affiliations

Merck and Co., Inc., Kenilworth, NJ, USA.Merck and Co., Inc., Kenilworth, NJ, USA.Merck and Co., Inc., Kenilworth, NJ, USA.Hartford Hospital, Hartford, CT, USA.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26096377

Citation

Xiao, Alan J., et al. "Ceftolozane/tazobactam Pharmacokinetic/pharmacodynamic-derived Dose Justification for Phase 3 Studies in Patients With Nosocomial Pneumonia." Journal of Clinical Pharmacology, vol. 56, no. 1, 2016, pp. 56-66.
Xiao AJ, Miller BW, Huntington JA, et al. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016;56(1):56-66.
Xiao, A. J., Miller, B. W., Huntington, J. A., & Nicolau, D. P. (2016). Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. Journal of Clinical Pharmacology, 56(1), 56-66. https://doi.org/10.1002/jcph.566
Xiao AJ, et al. Ceftolozane/tazobactam Pharmacokinetic/pharmacodynamic-derived Dose Justification for Phase 3 Studies in Patients With Nosocomial Pneumonia. J Clin Pharmacol. 2016;56(1):56-66. PubMed PMID: 26096377.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. AU - Xiao,Alan J, AU - Miller,Benjamin W, AU - Huntington,Jennifer A, AU - Nicolau,David P, Y1 - 2015/08/25/ PY - 2015/03/23/received PY - 2015/06/02/accepted PY - 2015/6/23/entrez PY - 2015/6/23/pubmed PY - 2016/10/7/medline KW - Pseudomonas aeruginosa KW - ceftolozane/tazobactam KW - dose justification KW - epithelial lining fluid KW - nosocomial pneumonia KW - probability of target attainment SP - 56 EP - 66 JF - Journal of clinical pharmacology JO - J Clin Pharmacol VL - 56 IS - 1 N2 - Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs. SN - 1552-4604 UR - https://www.unboundmedicine.com/medline/citation/26096377/Ceftolozane/tazobactam_pharmacokinetic/pharmacodynamic_derived_dose_justification_for_phase_3_studies_in_patients_with_nosocomial_pneumonia_ L2 - https://doi.org/10.1002/jcph.566 DB - PRIME DP - Unbound Medicine ER -