Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children
11/2017
Journal Article
Authors:
Autmizguine, J.;
Melloni, C.;
Hornik, C. P.;
Dallefeld, S.;
Harper, B.;
Yogev, R.;
Sullivan, J. E.;
Atz, A. M.;
Al-Uzri, A.;
Mendley, S.;
Poindexter, B.;
Mitchell, J.;
Lewandowski, A.;
Delmore, P.;
Cohen-Wolkowiez, M.;
Gonzalez, D.
Volume:
62
Issue:
1
Journal:
Antimicrob Agents Chemother
PMID:
29084742
URL:
https://www.ncbi.nlm.nih.gov/pubmed/29084742
Keywords:
Adolescent Adult Anti-Bacterial Agents/*pharmacokinetics Child Child, Preschool Female Humans Infant Infant, Newborn Male Methicillin-Resistant Staphylococcus aureus/drug effects Prospective Studies Staphylococcal Infections/drug therapy
Trimethoprim, Sulfamethoxazole Drug Combination/*pharmacokinetics Young Adult children infants methicillin-resistant Staphylococcus aureus pharmacokinetics sulfamethoxazole trimethoprim
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.
