title: Population Pharmacokinetics of Gentamicin in Mexican Children With Severe Malnutrition.
abstract: BACKGROUND
  To develop a population pharmacokinetic model of gentamicin in children with complicated severe malnutrition and to study the influence of covariates (weight and age) on pharmacokinetic indices. In addition, we use the model to perform Monte Carlo simulations to explore the efficacy of several dosage regimens.
  
  
  METHODS
  Twenty-six children with severe complicated malnutrition were studied. Ninety-six samples of gentamicin plasma concentrations, obtained from 0.5 to 8 hours after intravenous dosing, were analyzed. Population pharmacokinetic models were built using the program Monolix 4.2 (Lixoft, Antony, France). Monte Carlo simulations were performed to evaluate optimal dosage regimens, using the final pharmacokinetic model, based on the probability of pharmacokinetic-pharmacodynamic target attainment.
  
  
  RESULTS
  The concentration-time data were fitted best to 1-compartment model. The estimated population clearance was 1.1 L/h, and the volume of distribution was 2.23 L, with an interindividual variability of 47.2% and 35.6%, respectively. The final models for the clearance and volume of distribution were as follows: CL (L/h) = CL = 1.15 (age/median age) and V (L) = 2.33 (weight/median weight). In Monte Carlo simulations, gentamicin given in dosages of 7.5 to 15 mg/kg optical density was effective in achieving the pharmacodynamic target Cmax:minimal inhibitory concentration >10 for minimal inhibitory concentrations ≤2.5 mg/L, with a probability lower than 1% for Cmin >1 mg/L.
  
  
  CONCLUSIONS
  Based on the available evidence, an intravenous dose of 7.5 to 15 mg/kg once daily in children with complicated severe malnutrition and normal renal function ensures high probability of efficacy and low risk of nephrotoxicity, which gives further support to the recommendations issued by the World Health Organization treatment for this patient population.
authors.affiliation: From the *Department of Pharmacogenetics, Instituto Politécnico Nacional CIIDIR-Unidad Durango, Durango, Dgo, México; †Department of Clinical Pharmacology, Instituto Nacional de Pediatría, Ciudad de México, México; ‡Department of Respiratory Critical Care, Benemérita Universidad Autónoma de Puebla, Puebla, México; §Instituto Nacional de Enfermedades Respiratorias, Ciudad de México, México.
authors.forename: Ismael
authors.initials: I
authors.lastname: Lares-Asseff
authors.forename: Ma Gabriela
authors.initials: MG
authors.lastname: Pérz-Guillé
authors.forename: Guadalupe A
authors.initials: GA
authors.lastname: Camacho Vieyra
authors.forename: Adrián Guillé
authors.initials: AG
authors.lastname: Pérez
authors.forename: Natalia Barradas
authors.initials: NB
authors.lastname: Peregrina
authors.forename: Gustavo
authors.initials: G
authors.lastname: Lugo Goytia
mesh_terms: D016000:Cluster Analysis; D005260:Female; D005839:Gentamicins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D012189:Retrospective Studies; D000067011:Severe Acute Malnutrition
chemical_list: D005839:Gentamicins