The use of extrapolation based on modeling and simulation to support high-dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft-tissue infections.

Autor: Chan PLS; Pfizer, Sandwich, Kent, UK., McFadyen L; Pfizer, Sandwich, Kent, UK., Quaye A; Pfizer, Tadworth, Surrey, UK., Leister-Tebbe H; Pfizer, Collegeville, Pennsylvania, USA., Hendrick VM; Pfizer, Sandwich, Kent, UK., Hammond J; Pfizer, Collegeville, Pennsylvania, USA., Raber S; Pfizer, La Jolla, California, USA.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2021 Jun; Vol. 10 (6), pp. 551-563. Date of Electronic Publication: 2021 May 01.
DOI: 10.1002/psp4.12608
Abstrakt: A model-informed drug development approach was used to select ceftaroline fosamil high-dose regimens for pediatric patients with complicated skin and soft-tissue infections caused by Staphylococcus aureus with a ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady-state ceftaroline concentrations were simulated using a population pharmacokinetics (PK) model for ceftaroline fosamil and ceftaroline including data from 304 pediatric subjects and 944 adults. Probability of target attainment (PTA) for various simulated pediatric high-dose regimens and renal function categories were calculated based on patients achieving 35% fT>MIC (S. aureus PK/pharmacodynamic target for 2-log 10 bacterial killing). For extrapolation of efficacy, simulated exposures and PTA were compared to adults with normal renal function receiving high-dose ceftaroline fosamil (600 mg 2-h infusions every 8 h). For safety, predicted ceftaroline exposures were compared with observed pediatric and adult data. Predicted ceftaroline exposures for the approved pediatric high-dose regimens (12, 10, or 8 mg/kg by 2-h infusions every 8 h for patients aged >2 to <18 years with normal/mild, moderate, or severe renal impairment, respectively; 10 mg/kg by 2-h infusions every 8 h for patients aged ≥2 months to <2 years with normal renal function/mild impairment) were well matched to adults with normal renal function. Median predicted maximum concentration at steady state (C max,ss ) and area under the plasma concentration-time curve over 24 h at steady state pediatric to adult ratios were 0.907-1.33 and 0.940-1.41, respectively. PTAs (>99% and ≥81% for MICs of 2 and 4 mg/L, respectively) matched or exceeded the adult predictions. Simulated C max,ss values were below the maximum observed data in other indications, including a high-dose pediatric pneumonia trial, which reported no adverse events related to high exposure.
(© 2021 Pfizer R&D UK Limited. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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