Semimechanistic modeling of copeptin and aldosterone kinetics and dynamics in response to rehydration treatment for diabetic ketoacidosis in children.

Autor: Otto ME; Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.; Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands., Burckhardt MA; Pediatric Endocrinology and Diabetology, University Children's Hospital Basel, University of Basel, Basel, Switzerland.; Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland., Szinnai G; Pediatric Endocrinology and Diabetology, University Children's Hospital Basel, University of Basel, Basel, Switzerland.; Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland., Pfister M; Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.; Certara, Princeton, New Jersey, USA., Gotta V; Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2023 Feb; Vol. 12 (2), pp. 207-220. Date of Electronic Publication: 2022 Dec 12.
DOI: 10.1002/psp4.12891
Abstrakt: Diabetic ketoacidosis (DKA), a frequent complication of type 1 diabetes (T1D), is characterized by hyperosmolar hypovolemia. The response of water-regulating hormones arginine vasopressin (AVP; antidiuretic hormone) and aldosterone to DKA treatment in children is not well understood, although they may have potential as future diagnostic, prognostic, and/or treatment monitoring markers in diabetic patients. We aimed to characterize the dynamics of the response in copeptin (marker for AVP) and aldosterone secretion to rehydration treatment in pediatric patients with DKA. Data originated from a prospective, observational, multicenter study including 28 pediatric T1D patients treated for DKA (median age, 11.5 years; weight, 35 kg). Serial measurements of hormone levels were obtained during 72 h following rehydration start. Semimechanistic pharmacometric modeling was used to analyze the kinetic/dynamic relationship of copeptin and aldosterone secretion in response to the correction of hyperosmolality and hypovolemia, respectively. Modeling revealed different sensitivities for osmolality-dependent copeptin secretion during the first 72 h of rehydration, possibly explained by an osmotic shift introduced by hypovolemia. Response in aldosterone secretion to the correction of hypovolemia seemed to be delayed, which was well described by an extra upstream turnover compartment, possibly representing chronic upregulation of aldosterone synthase (cytochrome P450 11B2). In conclusion, semimechanistic modeling provided novel physiological insights in hormonal water regulation in pediatric patients during DKA treatment, providing rationale to further evaluate the potential of monitoring copeptin, but not aldosterone due to its delayed response, for future optimization of rehydration treatment to reduce the risk of acute complications such as cerebral edema.
(© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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