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Interrelationships Among Cortisol, 17-Hydroxyprogesterone, and Androstenendione Exposures in the Management of Children With Congenital Adrenal Hyperplasia
  1. Kyriakie Sarafoglou, MD*,
  2. Cheryl L. Zimmerman, PhD,
  3. Maria T. Gonzalez-Bolanos, MD*,
  4. Brian A. Willis, PhD,
  5. Richard Brundage, PhD
  1. From the *Department of Pediatrics, University of Minnesota Children’s Hospital; † College of Pharmacy, University of Minnesota, Minneapolis, MN; and ‡Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
  1. Received August 13, 2014, and in revised form September 17, 2014.
  2. Accepted for publication October 3, 2014.
  3. Reprints: Kyriakie Sarafoglou, MD, Division of Pediatric Endocrinology, Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota Children’s Hospital, East Bldg., Rm MB671, 2450 Riverside Avenue, Minneapolis, MN 55454. E-mail: saraf010{at}umn.edu.

Abstract

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated.

Objectives (1) Assess individual oral hydrocortisone pharmacokinetics; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; (3) determine potential individualized treatment regimens based on each subject’s pharmacokinetic and pharmacodynamic parameters.

Methods Thirty-four patients (18 boys, 16 girls, aged 1.4 to 18.1 years) with CAH underwent 6-hour pharmacokinetic studies. Results were analyzed by noncompartmental methods to obtain the area under the curve (AUC) for cortisol, 17-hydroxyprogesterone, and androstenedione; maximum concentration and time-to-maximum concentration for cortisol; and minimum and time-to-minimum concentration for 17-hydroxyprogesterone and androstenedione.

Results Mean (SD) cortisol half-life and Cmax were 1.01 (0.20) hours and 24.4 (5.4) μg/dL, respectively. The AUCs for cortisol, 17-hydroxyprogesterone and androstenedione were 40.8 (14.5) μg hour/dL, 29,490 (23,539) ng hour/dL, and 680 (795) ng hour/dL, respectively. No significant relationships existed between cortisol AUCs and the AUCs of either 17-hydroxyprogesterone (P = 0.32) or androstenedione (P = 0.99); nor were there differences between the change-from-baseline concentrations for cortisol with either 17-hydroxyprogesterone (P = 0.80) or androstenedione (P = 0.40). Cortisol simulations indicated that although four daily doses decreased 24-hour hypercortisolemia and hypocortisolemia, substantial periods of each remained.

Conclusions Concentration profiles of cortisol, 17-hydroxyprogesterone, and androstenedione are highly variable in children with CAH, and knowledge of them can assist in personalizing the therapy of CAH patients. Hydrocortisone’s rapid half-life and the lack of a sustained-released product make it difficult to closely approximate normal circadian profiles.

Key Words
  • cortisol
  • pharmacokinetics
  • congenital adrenal hyperplasia
  • hydrocortisone

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