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    Population pharmacokinetics of trimethoprim- sulfamethoxazole in infants and children

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    Author
    Autmizguine, J.
    Melloni, C.
    Hornik, C.P.
    Date
    2018
    Journal
    Antimicrobial Agents and Chemotherapy
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1128/AAC.01813-17
    Abstract
    Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in 90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/ day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to 21 years and 0 to 6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter. Copyright Copyright 2017 American Society for Microbiology. All Rights Reserved.
    Sponsors
    This work was funded under National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I for the Pediatric Trials Network (PI, Danny Benjamin).
    Keyword
    Children
    Infants
    Methicillin-resistant Staphylococcus aureus
    Pharmacokinetics
    Sulfamethoxazole
    Trimethoprim
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85039793051&doi=10.1128%2fAAC.01813-17&partnerID=40&md5=93a9ae34f315898456803c5d83f30dbc; http://hdl.handle.net/10713/9695
    ae974a485f413a2113503eed53cd6c53
    10.1128/AAC.01813-17
    Scopus Count
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