Mélanie Rapp1,2,3, Saïk Urien4,5, Frantz Foissac4,5, Agathe Béranger5,6, Naïm Bouazza4,5, Sihem Benaboud5,7, Emmanuelle Bille8, Yi Zheng5,6, Inès Gana5,6, Florence Moulin6, Fabrice Lesage6, Sylvain Renolleau6, Jean Marc Tréluyer4,5,7, Déborah Hirt5,7, Mehdi Oualha5,6. 1. Unité de recherche Clinique-Centre d'Investigation Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. mehdi.oualha@aphp.fr. 2. EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris Descartes, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. mehdi.oualha@aphp.fr. 3. Service de réanimation et surveillance continue médico-chirurgicale, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. mehdi.oualha@aphp.fr. 4. Unité de recherche Clinique-Centre d'Investigation Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. 5. EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris Descartes, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. 6. Service de réanimation et surveillance continue médico-chirurgicale, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. 7. Service de pharmacologie clinique, Hôpital Cochin, Université Paris Descartes, Sorbonne-Paris Cité, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. 8. Laboratoire de microbiologie, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France.
Abstract
PURPOSE: We aimed to develop a meropenem population pharmacokinetic (PK) model in critically ill children and simulate dosing regimens in order to optimize patient exposure. METHODS: Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach. RESULTS: Forty patients with an age of 16.8 (1.4-187.2) months, weight of 9.1 (3.8-59) kg, and estimated glomerular filtration rate (eGFR) of 151 (19-440) mL/min/1.73 m2 were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first-order elimination. Body weight (BW), eGFR, and CRRT were covariates explaining the between-subject variabilities on central/peripheral volume of distribution (V1/V2), inter-compartment clearance (Q), and clearance (CL): V1i = V1pop × (BW/70)1, Qi = Qpop × (BW/70)0.75, V2i = V2pop × (BW/70)1, CLi = (CLpop × (BW/70)0.75) × (eGFR/100)0.378) for patients without CRRT and CLi = (CLpop × (BW/70)0.75) × 0.9 for patients with CRRT, where CLpop, V1pop, Qpop, and V2pop are 6.82 L/h, 40.6 L, 1 L/h, and 9.2 L respectively normalized to a 70-kg subject. Continuous infusion, 60 and 120 mg/kg per day, is the most adequate dosing regimen to attain the target of 50% fT > MIC and 100% fT > MIC for patients infected by bacteria with high minimum inhibitory concentration (MIC) value (> 4 mg/L) without risk of accumulation except in children with severe renal failure. CONCLUSION: Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.
PURPOSE: We aimed to develop a meropenem population pharmacokinetic (PK) model in critically illchildren and simulate dosing regimens in order to optimize patient exposure. METHODS:Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem PK was investigated using a non-linear mixed-effect modeling approach. RESULTS: Forty patients with an age of 16.8 (1.4-187.2) months, weight of 9.1 (3.8-59) kg, and estimated glomerular filtration rate (eGFR) of 151 (19-440) mL/min/1.73 m2 were included. Eleven patients received continuous replacement renal therapy (CRRT). Concentration-time courses were best described by a two-compartment model with first-order elimination. Body weight (BW), eGFR, and CRRT were covariates explaining the between-subject variabilities on central/peripheral volume of distribution (V1/V2), inter-compartment clearance (Q), and clearance (CL): V1i = V1pop × (BW/70)1, Qi = Qpop × (BW/70)0.75, V2i = V2pop × (BW/70)1, CLi = (CLpop × (BW/70)0.75) × (eGFR/100)0.378) for patients without CRRT and CLi = (CLpop × (BW/70)0.75) × 0.9 for patients with CRRT, where CLpop, V1pop, Qpop, and V2pop are 6.82 L/h, 40.6 L, 1 L/h, and 9.2 L respectively normalized to a 70-kg subject. Continuous infusion, 60 and 120 mg/kg per day, is the most adequate dosing regimen to attain the target of 50% fT > MIC and 100% fT > MIC for patientsinfected by bacteria with high minimum inhibitory concentration (MIC) value (> 4 mg/L) without risk of accumulation except in children with severe renal failure. CONCLUSION: Continuous infusion allows reaching the fT > MIC targets safely in children with normal or increased renal clearance.
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