Population pharmacokinetics of trimethoprim- sulfamethoxazole in infants and children

Pediatric Trials Network Steering Committee

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere01813
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Sulfamethoxazole Drug Combination Trimethoprim
Pharmacokinetics
Population
Trimethoprim
Oral Administration
Pneumocystis Infections
Bacteria
Community-Acquired Infections
Pneumocystis carinii
Methicillin-Resistant Staphylococcus aureus
Serum Albumin
Small Intestine
Creatinine
Body Weight
Prospective Studies
Weights and Measures

Keywords

  • Children
  • Infants
  • Methicillin-resistant Staphylococcus aureus
  • Pharmacokinetics
  • Sulfamethoxazole
  • Trimethoprim

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Population pharmacokinetics of trimethoprim- sulfamethoxazole in infants and children. / Pediatric Trials Network Steering Committee.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 1, e01813, 01.01.2018.

Research output: Contribution to journalArticle

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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.",
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AU - Pediatric Trials Network Steering Committee

AU - Autmizguine, Julie

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AU - Dallefeld, Samantha

AU - Harper, Barrie

AU - Yogev, Ram

AU - Sullivan, Janice E.

AU - Atz, Andrew M.

AU - Al-Uzri, Amira

AU - Mendley, Susan

AU - Poindexter, Brenda

AU - Mitchell, Jeff

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N2 - 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.

AB - 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.

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