Curriculum vitae

Forschungslinie 2: Pharmacometric data analysis

“Optimisation of cortisol substitution therapy by employing pharmacometric methods”

Exogenous cortisol (as drug substance also known as hydrocortisone) has been used for decades as substitution therapy in treatment of adrenocortical insufficiency. The primary adrenocortical insufficiency in children and adolescents is most commonly caused by congenital adrenal hyperplasia (CAH). CAH is a group of autosomal recessively inherited metabolic diseases comprising a disorder of the cortisol biosynthesis due to a deficiency of the enzyme steroid 21-hydroxylase. Consequences are an overproduction of androgens and occurrence of symptoms such as virilisation, hirsutism, premature pseudo puberty, prematurely ended longitudinal growth as well as electrolyte imbalance caused by underproduction of mineralocorticoids.

The glucocorticoid of choice for therapy of CAH is hydrocortisone because of its short half-life and low potency. The substitution therapy requires particular caution as too high cortisol concentrations increase the risk for Cushing’s syndrome, whereas too low cortisol concentrations can result in Addisonian crisis or can lead to disease progression. Furthermore, the hypothalamic-pituitary-adrenal (HPA) axis causes a circadian rhythm of the cortisol biosynthesis, whereby the cortisol concentration reaches its maximum in the morning and decreases over the course of the day. For a successful suppression of the androgen overproduction and mineralocorticoid underproduction, it is important to mimic these concentration fluctuations and electrolyte homeostasis by means of the substitution therapy. Therefore, the substitution therapy with hydrocortisone, especially in paediatric patients, requires therapy optimisation, which can be achieved by means of therapeutic drug monitoring (TDM). Within TDM the drug concentration is measured regularly in the plasma and, if necessary, the dose is adjusted in accordance to measured exposure in order to obtain an optimal effect.

Pharmacometrics, in particular the nonlinear mixed-effects modelling approach, offers a powerful means for therapy optimisation. In our working group data from clinical studies with initially healthy adults and later in paediatric CAH patients were analysed in order to understand and to characterise the underlying mechanisms of the pharmacokinetics (PK) of hydrocortisone in form of both licensed and new formulations. On that basis, in order to describe and enable prediction of the relationships between the PK and pharmacodynamics (PD) of hydrocortisone, a semi-mechanistic PK/PD and disease model was established.

Based on these results, the objective of my PhD project is to develop more comprehensive pharmacometric models by using data from further clinical studies, literature and repositories. In order to obtain options for an improved and more successful dosing regimen, further knowledge on the PK and PD of hydrocortisone linked to characteristics of the dynamics of the physiological and pathophysiological networks in the patient’s body shall be gained. Moreover, in order to measure the outcome of the substitution therapy or the progression of the disease, inter alia, the cortisol precursor 17-α-hydroxyprogesterone (17-OHP) and the testosterone precursor androstendione shall be used as biomarkers during the clinical studies. Finally, the development of new physiologic and mechanistically based models shall contribute to the therapy optimisation of CAH in paediatric patients. The ultimate goal of this project is the establishment and evaluation of model-informed TDM, which can be implemented into clinical routine.