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Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation.

Publication ,  Journal Article
Commander, SJ; Wu, H; Boakye-Agyeman, F; Melloni, C; Hornik, CD; Zimmerman, K; Al-Uzri, A; Mendley, SR; Harper, B; Cohen-Wolkowiez, M ...
Published in: J Clin Pharmacol
March 2021

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose-exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03-19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11-1.8 kg) and the median number of doses recorded per participant was 5 (1-8). HCTZ PK was well characterized by a 1-compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.

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Published In

J Clin Pharmacol

DOI

EISSN

1552-4604

Publication Date

March 2021

Volume

61

Issue

3

Start / End Page

368 / 377

Location

England

Related Subject Headings

  • Young Adult
  • Prospective Studies
  • Pharmacology & Pharmacy
  • Pediatric Obesity
  • Organic Anion Transporters, Sodium-Independent
  • Organic Anion Transport Protein 1
  • Nonlinear Dynamics
  • Models, Biological
  • Male
  • Infant, Newborn
 

Citation

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Commander, S. J., Wu, H., Boakye-Agyeman, F., Melloni, C., Hornik, C. D., Zimmerman, K., … Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee, . (2021). Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation. J Clin Pharmacol, 61(3), 368–377. https://doi.org/10.1002/jcph.1739
Commander, Sarah Jane, Huali Wu, Felix Boakye-Agyeman, Chiara Melloni, Chi Dang Hornik, Kanecia Zimmerman, Amira Al-Uzri, et al. “Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation.J Clin Pharmacol 61, no. 3 (March 2021): 368–77. https://doi.org/10.1002/jcph.1739.
Commander SJ, Wu H, Boakye-Agyeman F, Melloni C, Hornik CD, Zimmerman K, et al. Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation. J Clin Pharmacol. 2021 Mar;61(3):368–77.
Commander, Sarah Jane, et al. “Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation.J Clin Pharmacol, vol. 61, no. 3, Mar. 2021, pp. 368–77. Pubmed, doi:10.1002/jcph.1739.
Commander SJ, Wu H, Boakye-Agyeman F, Melloni C, Hornik CD, Zimmerman K, Al-Uzri A, Mendley SR, Harper B, Cohen-Wolkowiez M, Hornik CP, Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee. Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation. J Clin Pharmacol. 2021 Mar;61(3):368–377.

Published In

J Clin Pharmacol

DOI

EISSN

1552-4604

Publication Date

March 2021

Volume

61

Issue

3

Start / End Page

368 / 377

Location

England

Related Subject Headings

  • Young Adult
  • Prospective Studies
  • Pharmacology & Pharmacy
  • Pediatric Obesity
  • Organic Anion Transporters, Sodium-Independent
  • Organic Anion Transport Protein 1
  • Nonlinear Dynamics
  • Models, Biological
  • Male
  • Infant, Newborn