Universität zu Köln

Stachanow, Viktoria, Neumann, Uta, Blankenstein, Oliver, Fuhr, Uwe, Huisinga, Wilhelm, Michelet, Robin ORCID: 0000-0002-5485-607X, Reisch, Nicole and Kloft, Charlotte (2021). Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling. Eur. J. Endocrinol., 185 (3). S. 365 - 375. BRISTOL: BIOSCIENTIFICA LTD. ISSN 1479-683X

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Abstract

Context: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 mu g/kg/day has been used since decades without examination in clinical trials and is thus still considered experimental. Objective: As the traditional dexamethasone dose potentially causes adverse effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation framework. Methods: Based on a published dexamethasone dataset, a nonlinear mixed-effects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n = 1000), a typical pregnant population (n = 124) was split into two dosing arms receiving either the traditional 20 mu g/kg/day dexamethasone dose or reduced doses between 5 and 10 mu g/kg/day. Target maternal dexamethasone concentrations, identified from the literature, served as a threshold to be exceeded by 90% of mothers at a steady state to ensure foetal hypothalamic-pituitary-adrenal axis suppression. Results: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 mu g/kg/day to be the minimum effective dose and thus our suggested dose. Conclusions: We conclude that the traditional dexamethasone dose is three-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stachanow, Viktoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumann, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Blankenstein, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Huisinga, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Michelet, Robin UNSPECIFIED orcid.org/0000-0002-5485-607X UNSPECIFIED Reisch, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloft, Charlotte UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-595013
DOI:	10.1530/EJE-21-0395
Journal or Publication Title:	Eur. J. Endocrinol.
Volume:	185
Number:	3
Page Range:	S. 365 - 375
Date:	2021
Publisher:	BIOSCIENTIFICA LTD
Place of Publication:	BRISTOL
ISSN:	1479-683X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEPENDENT PHARMACOKINETICS; TREATED CHILDREN; RISK; GLUCOCORTICOIDS; DIAGNOSIS; CORTISOL; PHARMACODYNAMICS; BIOAVAILABILITY; MECHANISM; BINDING Multiple languages Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59501