Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling

in European Journal of Endocrinology
View More View Less
  • 1 Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
  • | 2 Graduate Research Training Program PharMetrX, Berlin, Germany
  • | 3 Institute for Experimental Paediatric Endocrinology, Charité-Universitätsmedizin, Berlin, Germany
  • | 4 Department I of Pharmacology, Center for Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • | 5 Institute of Mathematics, Universität Potsdam, Golm, Germany
  • | 6 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany

Correspondence should be addressed to C Kloft Email: charlotte.kloft@fu-berlin.de

*(N Reisch and C Kloft contributed equally as senior authors)

Restricted access

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 µg/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 µg/kg/day dexamethasone dose or reduced doses between 5 and 10 µg/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 µg/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.

Supplementary Materials

    • Supplemental Information
    • Supplementary Table 1. Pharmacokinetic parameter estimates of developed dexamethasone model
    • Supplementary Figure 1. Goodness-of-fit plots of the developed dexamethasone (Dex) pharmacokinetic model. A: Population-predicted Dex concentrations versus measured Dex concentrations, B: Individual Dex predictions versus measured Dex concentrations, C: Conditional weighted residuals (CWRES) versus population-predicted Dex concentrations, D: Conditional weighted residuals versus time. Solid line: Line of identity (A and B), CWRES=0 (C and D).
    • Supplementary Figure 2. Visual predictive check (n=1000 simulations) for the dexamethasone (Dex) pharmacokinetic model. Lines: the 5th (upper dashed), 50th (solid) and 95th (lower dashed) percentiles of measured (black) and simulated (grey) Dex concentrations; grey shaded areas: 95% confidence interval around the simulated percentiles. Circles: Measured Dex concentrations. Horizontal line: Lower limit of quantification.
    • Supplementary Figure 3. Dexamethasone (Dex) concentration–time profiles after administration of reduced doses with 5 (A), 6 (B), 9 (C) and 10 (D) µg/kg/d for light (n=62, 50-72 kg) body weight group with n=1000 simulations. 10th percentiles (black lines), medians (dark grey lines) and 90th percentiles (light grey lines). Dashed horizontal lines: Dex threshold concentration if Dex is 50- (upper line) or 80-fold (lower line) more potent than cortisol, light grey boxes: Minimum Dex concentration at steady state. Arrows: Dex dose administrations before (dashed arrows) and after (solid line arrows) steady state.
    • Supplementary Figure 4. Sensitivity analysis for foetal:maternal dexamethasone concentration ratio. Simulated 10th percentile dexamethasone (Dex) profiles of light (n=62, 50-72 kg) body weight group after administration of reduced doses with 9 (A) and 10 (B) µg/kg/d, if foetal:maternal Dex concentration ratio was 0.3 (top) or 0.25 (bottom) instead of 0.45. Dashed horizontal lines: Dex threshold concentration if Dex is 50- (upper line) or 80-fold (lower line) more potent than cortisol, light grey boxes: Minimum Dex concentration at steady state. Arrows: Dex dose administrations before (dashed arrows) and after (solid line arrows) steady state.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 765 765 194
Full Text Views 69 69 3
PDF Downloads 86 86 4
  • 1

    Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Hassan Murad MH & Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2018 103 40434088. (https://doi.org/10.1210/jc.2018-01865)

    • Search Google Scholar
    • Export Citation
  • 2

    David M, Forest MG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Journal of Pediatrics 1984 105 799803. (https://doi.org/10.1016/s0022-3476(8480310-8)

    • Search Google Scholar
    • Export Citation
  • 3

    Forest MG Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Current Opinion in Endocrinology and Diabetes 1997 4 209217. (https://doi.org/10.1097/00060793-199706000-00005)

    • Search Google Scholar
    • Export Citation
  • 4

    Forest MG Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Human Reproduction Update 2004 10 469485. (https://doi.org/10.1093/humupd/dmh047)

    • Search Google Scholar
    • Export Citation
  • 5

    New MI, Carlson A, Obeid J, Marshall I, Cabrera MS, Goseco A, Lin-Su K, Putnam AS, Wei JQ, Wilson RC. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. Journal of Clinical Endocrinology and Metabolism 2001 86 56515657. (https://doi.org/10.1210/jcem.86.12.8072)

    • Search Google Scholar
    • Export Citation
  • 6

    Miller WL Fetal endocrine therapy for congenital adrenal hyperplasia should not be done. Best Practice and Research: Clinical Endocrinology and Metabolism 2015 29 469483. (https://doi.org/10.1016/j.beem.2015.01.005)

    • Search Google Scholar
    • Export Citation
  • 7

    Hirvikoski T, Nordenstrm A, Wedell A, Ritzn M, Lajic S. Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: the Swedish experience and standpoint. Journal of Clinical Endocrinology and Metabolism 2012 97 18811883. (https://doi.org/10.1210/jc.2012-1222)

    • Search Google Scholar
    • Export Citation
  • 8

    New MI, Abraham M, Yuen T, Lekarev O. An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia. Seminars in Reproductive Medicine 2012 30 396399. (https://doi.org/10.1055/s-0032-1324723)

    • Search Google Scholar
    • Export Citation
  • 9

    Khulan B, Drake AJ. Glucocorticoids as mediators of developmental programming effects. Best Practice and Research: Clinical Endocrinology and Metabolism 2012 26 689700. (https://doi.org/10.1016/j.beem.2012.03.007)

    • Search Google Scholar
    • Export Citation
  • 10

    Hirvikoski T, Lindholm T, Lajic S, Nordenström A. Gender role behaviour in prenatally dexamethasone-treated children at risk for congenital adrenal hyperplasia – a pilot study. Acta Paediatrica 2011 100 e112e119. (https://doi.org/10.1111/j.1651-2227.2011.02260.x)

    • Search Google Scholar
    • Export Citation
  • 11

    Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Lajic S. Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems? European Journal of Endocrinology 2008 159 309316. (https://doi.org/10.1530/EJE-08-0280)

    • Search Google Scholar
    • Export Citation
  • 12

    Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Wedell A, Lajic S. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Journal of Clinical Endocrinology and Metabolism 2007 92 542548. (https://doi.org/10.1210/jc.2006-1340)

    • Search Google Scholar
    • Export Citation
  • 13

    Maryniak A, Ginalska-Malinowska M, Bielawska A, Ondruch A. Cognitive and social function in girls with congenital adrenal hyperplasia – influence of prenatally administered dexamethasone. Child Neuropsychology 2014 20 6070. (https://doi.org/10.1080/09297049.2012.745495)

    • Search Google Scholar
    • Export Citation
  • 14

    Meyer-Bahlburg HFL, Dolezal C, Baker SW, Carlson AD, Obeid JS, New MI. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. Journal of Clinical Endocrinology and Metabolism 2004 89 610614. (https://doi.org/10.1210/jc.2002-021129)

    • Search Google Scholar
    • Export Citation
  • 15

    Meyer-Bahlburg HFL, Dolezal C, Haggerty R, Silverman M, New MI. Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. European Journal of Endocrinology 2012 167 103110. (https://doi.org/10.1530/EJE-11-0789)

    • Search Google Scholar
    • Export Citation
  • 16

    Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 1995 20 439449. (https://doi.org/10.1016/0306-4530(9400070-0)

    • Search Google Scholar
    • Export Citation
  • 17

    Van’t Westeinde A, Karlsson L, Nordenström A, Padilla N, Lajic S. First-trimester prenatal dexamethasone treatment is associated with alterations in brain structure at adult age. Journal of Clinical Endocrinology and Metabolism 2020 105 dgaa340. (https://doi.org/10.1210/clinem/dgaa340)

    • Search Google Scholar
    • Export Citation
  • 18

    Van’t Westeinde A, Zimmermann M, Messina V, Karlsson L, Padilla N, Lajic S. First trimester DEX treatment is not associated with altered brain activity during working memory performance in adults. Journal of Clinical Endocrinology and Metabolism 2020 105 e4074e4082. (https://doi.org/10.1210/clinem/dgaa611)

    • Search Google Scholar
    • Export Citation
  • 19

    Karlsson L, Barbaro M, Ewing E, Gomez-Cabrero D, Lajic S. Epigenetic alterations associated with early prenatal dexamethasone treatment. Journal of the Endocrine Society 2019 3 250263. (https://doi.org/10.1210/js.2018-00377)

    • Search Google Scholar
    • Export Citation
  • 20

    Seckl JR Glucocorticoids, feto-placental 11β-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 1997 62 8994. (https://doi.org/10.1016/S0039-128X(9600165-1)

    • Search Google Scholar
    • Export Citation
  • 21

    Kari MA, Raivio KO, Stenman UH, Voutilainen R. Serum cortisol, dehydroepiandrosterone sulfate, and steroid-binding globulins in preterm neonates: effect of gestational age and dexamethasone therapy. Pediatric Research 1996 40 319324. (https://doi.org/10.1203/00006450-199608000-00021)

    • Search Google Scholar
    • Export Citation
  • 22

    Pillai GC, Mentré F, Steimer JL. Non-linear mixed effects modeling – from methodology and software development to driving implementation in drug development science. Journal of Pharmacokinetics and Pharmacodynamics 2005 32 161183. (https://doi.org/10.1007/s10928-005-0062-y)

    • Search Google Scholar
    • Export Citation
  • 23

    Michelet R, Melin J, Parra-Guillen ZP, Neumann U, Whitaker JM, Stachanow V, Huisinga W, Porter J, Blankenstein O & Ross RJ et al. Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children. European Journal of Endocrinology 2020 183 357368. (https://doi.org/10.1530/EJE-20-0231)

    • Search Google Scholar
    • Export Citation
  • 24

    Melin J, Parra-Guillen ZP, Michelet R, Truong T, Huisinga W, Hartung N, Hindmarsh P, Kloft C. Pharmacokinetic/pharmacodynamic evaluation of hydrocortisone therapy in pediatric patients with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2020 105 E1729E1740. (https://doi.org/10.1210/clinem/dgaa071)

    • Search Google Scholar
    • Export Citation
  • 25

    Melin J, Parra-Guillen ZP, Hartung N, Huisinga W, Ross RJ, Whitaker MJ, Kloft C. Predicting cortisol exposure from paediatric hydrocortisone formulation using a semi-mechanistic pharmacokinetic model established in healthy adults. Clinical Pharmacokinetics 2018 57 515527. (https://doi.org/10.1007/s40262-017-0575-8)

    • Search Google Scholar
    • Export Citation
  • 26

    Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT: Pharmacometrics and Systems Pharmacology 2012 1 e6. (https://doi.org/10.1038/psp.2012.4)

    • Search Google Scholar
    • Export Citation
  • 27

    R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing, 2019. (available at: https://www.R-project.org/)

    • Search Google Scholar
    • Export Citation
  • 28

    RStudio Team. RStudio: Integrated Development Environment for R. Boston, MA: Rstudio, PBC. 2020. (available at: http://www.rstudio.com/)

    • Search Google Scholar
    • Export Citation
  • 29

    Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides 1989–2009. Ellicott City, MD, USA: Icon Development Solutions, 2009.

  • 30

    Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit – a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Computer Methods and Programs in Biomedicine 2005 79 241257. (https://doi.org/10.1016/j.cmpb.2005.04.005)

    • Search Google Scholar
    • Export Citation
  • 31

    Keizer RJ, Benten M, Beijnen JH, Schellens JH, Huitema AD. Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM. Computer Methods and Programs in Biomedicine 2011 101 7279. (https://doi.org/10.1016/j.cmpb.2010.04.018)

    • Search Google Scholar
    • Export Citation
  • 32

    Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT: Pharmacometrics and Systems Pharmacology 2013 2 e38. (https://doi.org/10.1038/psp.2013.14)

    • Search Google Scholar
    • Export Citation
  • 33

    Owen JS, Fielder-Kelly J. Introduction to Population Pharmacokinetic/Pharmacodynamic Analysis with Nonlinear Mixed Effect Models. Hoboken, New Jersey: John Wiley & Sons, Inc., 2014.

    • Search Google Scholar
    • Export Citation
  • 34

    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS Journal 2011 13 143151. (https://doi.org/10.1208/s12248-011-9255-z)

    • Search Google Scholar
    • Export Citation
  • 35

    Queckenberg C, Wachall B, Erlinghagen V, Di Gion P, Tomalik-Scharte D, Tawab M, Gerbeth K, Fuhr U. Pharmacokinetics, pharmacodynamics, and comparative bioavailability of single, oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized, controlled, crossover study in healthy adult volunteers. Clinical Therapeutics 2011 33 18311841. (https://doi.org/10.1016/j.clinthera.2011.10.006)

    • Search Google Scholar
    • Export Citation
  • 36

    Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Viswanathan CT, Cook CE, McDowall RD. Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report. European Journal of Drug Metabolism and Pharmacokinetics 1991 16 249255. (https://doi.org/10.1007/BF03189968)

    • Search Google Scholar
    • Export Citation
  • 37

    Holford NHG A size standard for pharmacokinetics. Clinical Pharmacokinetics 1996 30 329332. (https://doi.org/10.2165/00003088-199630050-00001)

    • Search Google Scholar
    • Export Citation
  • 38

    Goto M, Hanley KP, Marcos J, Wood PJ, Wright S, Postle AD, Cameron IT, Mason JI, Wilson DI, Hanley NA. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. Journal of Clinical Investigation 2006 116 953960. (https://doi.org/10.1172/JCI25091)

    • Search Google Scholar
    • Export Citation
  • 39

    Rivkees SA, Crawford JD. Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth. Pediatrics 2000 106 767773. (https://doi.org/10.1542/peds.106.4.767)

    • Search Google Scholar
    • Export Citation
  • 40

    Tsuei SE, Petersen MC, Ashley JJ, McBride WG, Moore RG. Disposition of synthetic glucocorticoids. Clinical Pharmacology and Therapeutics 1980 28 8898. (https://doi.org/10.1038/clpt.1980.136)

    • Search Google Scholar
    • Export Citation
  • 41

    Cummings DM, Larijani GE, Conner DP, Ferguson RK, Rocci ML. Characterization of dexamethasone binding in normal and uremic human serum. DICP: the Annals of Pharmacotherapy 1990 24 229231. (https://doi.org/10.1177/106002809002400301)

    • Search Google Scholar
    • Export Citation
  • 42

    Gonciarz A, Kus K, Szafarz M, Walczak M, Zakrzewska A, Szymura-Oleksiak J. Capillary electrophoresis/frontal analysis versus equilibrium dialysis in dexamethasone sodium phosphate-serum albumin binding studies. Electrophoresis 2012 33 33233330. (https://doi.org/10.1002/elps.201200166)

    • Search Google Scholar
    • Export Citation
  • 43

    Loew D, Schuster O, Graul EH. Dose-dependent pharmacokinetics of dexamethasone. European Journal of Clinical Pharmacology 1986 30 225230. (https://doi.org/10.1007/BF00614309)

    • Search Google Scholar
    • Export Citation
  • 44

    Ke AB, Milad MA. Evaluation of maternal drug exposure following the administration of antenatal corticosteroids during late pregnancy using physiologically-based pharmacokinetic modeling. Clinical Pharmacology and Therapeutics 2019 106 164173. (https://doi.org/10.1002/cpt.1438)

    • Search Google Scholar
    • Export Citation
  • 45

    Dallmann A, Mian P, Anker Van den J, Allegaert K. Clinical pharmacokinetic studies in pregnant women and the relevance of pharmacometric tools. Current Pharmaceutical Design 2019 25 483495. (https://doi.org/10.2174/1381612825666190320135137)

    • Search Google Scholar
    • Export Citation
  • 46

    Dallmann A, Pfister M, van den Anker J, Eissing T. Physiologically based pharmacokinetic modeling in pregnancy: a systematic review of published models. Clinical Pharmacology and Therapeutics 2018 104 11101124. (https://doi.org/10.1002/cpt.1084)

    • Search Google Scholar
    • Export Citation
  • 47

    Li J, Chen R, Yao QY, Liu SJ, Tian XY, Hao CY, Lu W, Zhou TY. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model. Acta Pharmacologica Sinica 2018 39 472481. (https://doi.org/10.1038/aps.2017.153)

    • Search Google Scholar
    • Export Citation
  • 48

    Hochhaus G, Barth J, Al-Fayoumi S, Suarez S, Derendorf H, Hochhaus R, Möllmann H. Pharmacokinetics and pharmacodynamics of dexamethasone sodium-m-sulfobenzoate (DS) after intravenous and intramuscular administration: a comparison with dexamethasone phosphate (DP). Journal of Clinical Pharmacology 2001 41 425434. (https://doi.org/10.1177/00912700122010285)

    • Search Google Scholar
    • Export Citation
  • 49

    Ceccato F, Artusi C, Barbot M, Lizzul L, Pinelli S, Costantini G, Niero S, Antonelli G, Plebani M, Scaroni C. Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. Journal of Endocrinological Investigation 2020 43 11051113. (https://doi.org/10.1007/s40618-020-01197-6)

    • Search Google Scholar
    • Export Citation
  • 50

    Clayton PE, Oberfield SE, Martin Ritzén E, Sippell WG, Speiser PW, Hintz RL, Savage MO. Consensus: Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology. Journal of Clinical Endocrinology and Metabolism 2002 87 40484053. (https://doi.org/10.1210/jc.2002-020611)

    • Search Google Scholar
    • Export Citation
  • 51

    Technical Report: congenital adrenal hyperplasia. Section on Endocrinology and Committee on Genetics. Pediatrics 2000 106 15111518. (https://doi.org/10.1542/peds.106.6.1511)

    • Search Google Scholar
    • Export Citation