scholarly journals P93 Semi-mechanistic modelling of hydrocortisone pharmacokinetics in paediatric patients with adrenal insufficiency

2019 ◽  
Vol 104 (6) ◽  
pp. e55.3-e56
Author(s):  
V Stachanow ◽  
J Melin ◽  
R Michelet ◽  
O Blankenstein ◽  
U Neumann ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Plasma Concentrations ◽  
Mixed Effects ◽  
Phase Iii ◽  
Adrenal Crisis ◽  
List Type ◽  
Nonlinear Behaviour ◽  
Nonlinear Mixed Effects ◽  
Nonlinear Mixed Effects Model ◽  
Paediatric Patients

BackgroundPatients with congenital adrenal hyperplasia (CAH) have low to no biosynthesis of cortisol and require lifelong cortisol replacement. Optimisation of hydrocortisone (HC, synthetic cortisol) therapy in this population is important, since too low or high cortisol concentrations increase the risk of adrenal crisis or Cushing’s syndrome1. HC has nonlinear pharmacokinetics (PK) caused by saturable binding to corticosteroid binding globulin (CBG)2. The objective of this analysis was to extend an established paediatric HC PK-model3 with dried blood spot (DBS) data in order to further characterise the binding behaviour of HC in children.MethodsA semi-mechanistic adult PK model for a novel HC formulation4 has previously been reduced to a paediatric model using sparse plasma samples from a phase III study in 24 patients with adrenal insufficiency5. Plasma and DBS concentrations of cortisol were collected and additional DBS HC concentrations were obtained from a follow-up study. The relation between plasma and DBS samples was characterised by a graphical evaluation, after which nonlinear mixed-effects modelling was applied using NONMEM 7.4.ResultsPlasma concentrations of cortisol were substantially higher than the corresponding DBS concentrations. The plasma/DBS ratio ranged between 2 to 8 within and between children, while the relation between the cortisol DBS concentrations and cortisol plasma concentrations showed nonlinear behaviour mirroring the nonlinear binding kinetics to CBG.ConclusionsOur graphical analysis identified substantial differences and high inter- and intraindividual variabilities between plasma and DBS samples. A nonlinear mixed-effects model is being set up to quantify these findings and allow for further prediction of HC exposure. Afterwards, effect biomarkers can be included in order to evaluate cortisol replacement therapy and to optimise the HC treatment in paediatric patients.ReferencesSpeiser PW, et al. J Clin Endocrinol Metab 2010;95(9):4133–4160.Lentjes EG, WM, et al:J Clin Endocrinol Metab. 1999;84(2):682–687.Melin J:Dissertation 2017.Melin J, et al:Clin Pharmacokinet. 2018;57(4):515–527.Neumann U. et al:Clin Endocrinol. 2018;88(1):21–29.Disclosure(s)Nothing to disclose

scholarly journals A flexible nonlinear mixed effects model for HIV viral load rebound after treatment interruption

2020 ◽  
Vol 39 (15) ◽  
pp. 2051-2066 ◽  
Author(s):  
Rui Wang ◽  
Ante Bing ◽  
Cathy Wang ◽  
Yuchen Hu ◽  
Ronald J. Bosch ◽  
...  
Keyword(s):  
Viral Load ◽  
Treatment Interruption ◽  
Mixed Effects ◽  
Mixed Effects Model ◽  
Nonlinear Mixed Effects ◽  
Hiv Viral Load ◽  
Nonlinear Mixed Effects Model ◽  
Viral Load Rebound

scholarly journals A Nonlinear Mixed-Effects Model to Predict Stem Cumulative Biomass of Standing Trees

2011 ◽  
Vol 10 ◽  
pp. 215-221 ◽  
Author(s):  
Yaoxiang Li ◽  
Lichun Jiang ◽  
Mingyu liu
Keyword(s):  
Mixed Effects ◽  
Mixed Effects Model ◽  
Nonlinear Mixed Effects ◽  
Nonlinear Mixed Effects Model ◽  
Standing Trees

Nonlinear mixed-effects model for the dissolution assays of drugs

2004 ◽  
Vol 94 (2-3) ◽  
pp. 381-389 ◽  
Author(s):  
G. Frutos ◽  
M.C. Ruiz de Villa
Keyword(s):  
Mixed Effects ◽  
Mixed Effects Model ◽  
Nonlinear Mixed Effects ◽  
Nonlinear Mixed Effects Model

scholarly journals Retrospective analysis of chronic hepatitis C in untreated patients with nonlinear mixed effects model

2008 ◽  
Vol 01 (02) ◽  
pp. 85-90
Author(s):  
Jian Huang ◽  
Kathleen O’Sullivan ◽  
John Levis ◽  
Elizabeth Kenny-Walsh ◽  
Orla Crosbie ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Retrospective Analysis ◽  
Chronic Hepatitis C ◽  
Mixed Effects ◽  
Mixed Effects Model ◽  
Nonlinear Mixed Effects ◽  
Nonlinear Mixed Effects Model

scholarly journals Adrenal insufficiency in a woman secondary to standard-dose inhaled fluticasone propionate therapy

2014 ◽  
Vol 2014 ◽  
Author(s):  
Casey M Hay ◽  
Daniel I Spratt
Keyword(s):  
Fluticasone Propionate ◽  
Adrenal Insufficiency ◽  
Cortisol Level ◽  
Standard Dose ◽  
Clinical Signs ◽  
Unknown Origin ◽  
Adrenal Crisis ◽  
List Type ◽  
Morning Cortisol ◽  
Low Serum

Summary A 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Division of Reproductive Endocrinology to further evaluate an undetectable morning cortisol level discovered during the evaluation of a low serum DHEA-S level. She was asymptomatic other than having mild fatigue and weight gain. Her medication list included 220 μg of inhaled fluticasone propionate twice daily for asthma, which she was taking as prescribed. On presentation, the undetectable morning cortisol level was confirmed. A urinary measurement of fluticasone propionate 17β-carboxylic acid was markedly elevated. Fluticasone therapy was discontinued and salmeterol therapy initiated with supplemental hydrocortisone. Hydrocortisone therapy was discontinued after 2 months. A repeat urinary fluticasone measurement 4 months after the discontinuation of fluticasone therapy was undetectably low and morning cortisol level was normal at 18.0 μg/dl. Inhaled fluticasone is generally considered to be minimally systemically absorbed. This patient's only clinical evidence suggesting adrenal insufficiency was fatigue accompanying a low serum DHEA-S level. This case demonstrates that adrenal insufficiency can be caused by a routine dose of inhaled fluticasone. Missing this diagnosis could potentially result in adrenal crisis upon discontinuation of fluticasone therapy. Learning points Standard-dose inhaled fluticasone can cause adrenal insufficiency. Adrenal insufficiency should be considered in patients taking, or who have recently discontinued, inhaled fluticasone therapy and present with new onset of nonspecific symptoms such as fatigue, weakness, depression, myalgia, arthralgia, unexplained weight loss, and nausea that are suggestive of adrenal insufficiency. Adrenal insufficiency should be considered in postoperative patients who exhibit signs of hypoadrenalism after fluticasone therapy has been withheld in the perioperative setting. Routine screening for hypoadrenalism in patients without clinical signs or symptoms of adrenal insufficiency after the discontinuation of inhaled fluticasone therapy is not indicated due to the apparently low incidence of adrenal insufficiency caused by fluticasone.

Sign in / Sign up

Export Citation Format

Share Document