Population Pharmacokinetics of Trimethoprim |
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Antimicrob Agents Chemother. 2018 Jan; 62(1): e01813-17. Published online 2017 Dec 21. Prepublished online 2017 Oct 30. doi: 10.1128/AAC.01813-17PMCID: PMC5740321PMID: 29084742Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and ChildrenJulie Autmizguine,a Chiara Melloni,b Christoph P. Hornik,b Samantha Dallefeld,b Barrie Harper,b Ram Yogev,c Janice E. Sullivan,d Andrew M. Atz,e Amira Al-Uzri,f Susan Mendley,g Brenda Poindexter,h Jeff Mitchell,i Andrew Lewandowski,i Paula Delmore,j Michael Cohen-Wolkowiez,b and Daniel Gonzalezk, on behalf of the Pediatric Trials Network Steering CommitteeJulie Autmizguine aResearch Center, CHU Sainte-Justine, and Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada Find articles by Julie AutmizguineChiara MellonibDuke Clinical Research Institute, Durham, North Carolina, USA Find articles by Chiara MelloniChristoph P. HornikbDuke Clinical Research Institute, Durham, North Carolina, USA Find articles by Christoph P. HornikSamantha DallefeldbDuke Clinical Research Institute, Durham, North Carolina, USA Find articles by Samantha DallefeldBarrie HarperbDuke Clinical Research Institute, Durham, North Carolina, USA Find articles by Barrie HarperRam YogevcAnn and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA Find articles by Ram YogevJanice E. SullivandUniversity of Louisville, Norton Children's Hospital and Kosair Charities Pediatric Clinical Research Unit, Louisville, Kentucky, USA Find articles by Janice E. SullivanAndrew M. AtzeMedical University of South Carolina, Charleston, South Carolina, USA Find articles by Andrew M. AtzAmira Al-UzrifOregon Health and Science University, Portland, Oregon, USA Find articles by Amira Al-UzriSusan MendleygUniversity of Maryland School of Medicine, Baltimore, Maryland, USA Find articles by Susan MendleyBrenda PoindexterhPerinatal Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA Find articles by Brenda PoindexterJeff MitchelliEmmes Corporation, Rockville, Maryland, USA Find articles by Jeff MitchellAndrew LewandowskiiEmmes Corporation, Rockville, Maryland, USA Find articles by Andrew LewandowskiPaula DelmorejWesley Medical Center, Wichita, Kansas, USA Find articles by Paula DelmoreMichael Cohen-WolkowiezbDuke Clinical Research Institute, Durham, North Carolina, USA Find articles by Michael Cohen-WolkowiezDaniel GonzalezkUNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Find articles by Daniel GonzalezAuthor information Article notes Copyright and License information PMC DisclaimeraResearch Center, CHU Sainte-Justine, and Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, CanadabDuke Clinical Research Institute, Durham, North Carolina, USAcAnn and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USAdUniversity of Louisville, Norton Children's Hospital and Kosair Charities Pediatric Clinical Research Unit, Louisville, Kentucky, USAeMedical University of South Carolina, Charleston, South Carolina, USAfOregon Health and Science University, Portland, Oregon, USAgUniversity of Maryland School of Medicine, Baltimore, Maryland, USAhPerinatal Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USAiEmmes Corporation, Rockville, Maryland, USAjWesley Medical Center, Wichita, Kansas, USAkUNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USACorresponding author.Address correspondence to Daniel Gonzalez, [email protected] Autmizguine J, Melloni C, Hornik CP, Dallefeld S, Harper B, Yogev R, Sullivan JE, Atz AM, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D, on behalf of the Pediatric Trials Network Steering Committee. 2018. Population pharmacokinetics of trimethoprim-sulfamethoxazole in infants and children. Antimicrob Agents Chemother 62:e01813-17. https://doi.org/10.1128/AAC.01813-17.Received 2017 Aug 29; Accepted 2017 Oct 7.Copyright © 2017 American Society for Microbiology.All Rights Reserved.Associated DataSupplementary Materials Supplemental material supp_62_1_e01813-17__index.html (788 bytes)GUID: 25112A7D-1FBD-4276-8B2F-6213A8D16B73 AAC.01813-17_zac001186811s1.pdf (553K)GUID: 17450A1F-99C4-4FFA-A998-5AEF18277316 ABSTRACTTrimethoprim (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 |
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