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Apr 2, 2003
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Pharmacokinetic/pharmacodynamic analysis of data from a phase III trial of linezolid IV/PO for the treatment of resistant gram-positive bacterial infections in children

Abstract

Purpose: Linezolid (LZD), the first approved oxazolidinone, is effective against Gram-positive infections. Population pharmacokinetic/dynamic (PK/PD) analyses of Phase III data were conducted to evaluate exposureresponse relationships in children to support a multiple-dosing regimen.

Methods: Sparse samples were obtained from patients aged birth to 11 years given 10mg/kg LZD every 8 hours. Patients were allowed to switch to oral (microencapsulated suspension) after six intravenous (IV) doses. Previously developed population pharmacokinetic models were used to predict individual pharmacokinetic parameters and exposure by Bayesian method. Relationships between exposure and effectiveness (clinical/microbiological cure) and safety (hematologic labs, adverse events) were explored graphically.

Results: Mean ± SD age and weight were 35 ± 38 months and 13 ± 11 kg. All models predicted individual concentrations with minimal bias and misspecification. Mean ± SD area under the concentration-time curve (AUC 0-24) was 147 ± 87 μg•h/mL, lower than adult exposure (179 ± 62 μg•h/mL). Predicted time above MIC90 was 54 ± 25% and independent of administration route or age. End-of-treatment and follow-up clinical cure rates were 85% and 90%. Microbiologic success rate was 89%. There was no apparent association between exposures as measured by AUC and effectiveness or safety endpoints.

Conclusions: Previously developed models properly estimated exposure and verify dosing of 10 mg/kg every 8 hours in children aged birth to 11 years. Elimination of oral and IV LZD was comparable. Effectiveness and safety were independent of exposure.

American Society for Clinical Pharmacology and Therapeutics (ASCPT), Washington, DC, April 2003

Vo, M., Rubino, C., Cirincione, B., Bruss, J., Jungbluth, G.

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