dc.description.abstract
Pharmacometric approaches are commonly applied to increase the understanding of pharmacokinetics, pharmacodynamics, disease of a system and their interactions. These approaches are often used both in academia, industry and in the clinical setting to contribute to a more rational use of medicines. In the current thesis, pharmacometric approaches were used to assess the current dosing strategies in paediatric patients with adrenal insufficiency. Congenital adrenal hyperplasia (CAH) is a common kind of adrenal insufficiency resulting from a deficiency in 21-hydroxylase, which is an important enzyme in the cortisol synthesis pathway. This patient population represents a very vulnerable population with no/low endogenous synthesis of cortisol, thereby requiring lifelong substitution therapy with glucocorticoids from birth. Hydrocortisone is the recommended glucocorticoid in growing paediatric patients, since longer-acting glucocorticoids are associated with more reduction in final height. The aim of the treatment is to mimic the physiological circadian cortisol concentrations. Hydrocortisone is therefore administered two-four times daily, due to its relatively short terminal half-life (1.5 h). Monitoring treatment in CAH patients is important, since overtreatment (too high cortisol concentrations) may lead to Cushing’s syndrome and reduced final height, whereas undertreatment (too low cortisol concentrations) may lead to disease progression, virilisation in girls, electrolyte imbalances and increased risk for adrenal crisis. An increased mechanism-based understanding of the pharmacokinetics and pharmacokinetics/pharmacodynamics of hydrocortisone in this population may contribute to a more rational use of hydrocortisone in patients with adrenal insufficiency.
Firstly, rich phase 1 data from healthy adults administered a novel hydrocortisone formulation suitable for newborns (Infacort®), allowed for quantifying the pharmacokinetics in a semi-mechanistic way accounting for: i) constant cortisol baseline after dexamethasone suppression, ii) nonlinear plasma protein binding to CBG and linear binding (to e.g. albumin/erythrocytes) and iii) a saturable absorption process. This was the first semi-mechanistic PK model of hydrocortisone, which successfully could very well predict the observed data in paediatric patients with adrenal insufficiency (neonates to 6 years) administered Infacort.
Secondly, a reduced paediatric pharmacokinetic model was established on sparse phase 3 data from paediatric patients (neonates to 6 years), from which a slightly lower and higher clearance was observed in neonates and infants, respectively.
In a third step, data from a more clinical situation was used to further reduce the paediatric PK model to better describe the data in paediatric patients (7-17 years) with CAH administered licenced hydrocortisone tablets and intravenous hydrocortisone. In addition, concentrations from a clinically-relevant biomarker 17-hydroxyprogesterone (17-OHP), a precursor to cortisol which is elevated in patients with CAH, was used to establish a pharmacokinetic/pharmacodynamic model considering the cortisol-mediated inhibition of the 17-OHP synthesis and the circadian rhythm of 17-OHP. The established pharmacokinetic/pharmacodynamic model was also used to simulate cortisol and 17-OHP concentration-time profiles after three and four times daily administration of hydrocortisone tablets. None of the studied dosing regimens could well mimic the rhythm, but a four times daily dosing regimen was superior to a three times daily dosing regimen and resulted in higher cortisol concentrations in the morning. This analysis visualised the difficulties associated with mimicking the physiological cortisol concentrations after three or four times daily dosing. Since outcome measures, such as final height and disease progression are of primary interest, prospective studies should be performed to evaluate the impact of changing dosing regimen on these outcomes.
To conclude: treatment optimisation in patients with adrenal insufficiency is challenging especially in paediatrics but important to perform in order to possibly avoid disease progression, adrenal crisis or Cushing’s syndrome. An increased understanding regarding the pharmacokinetics of hydrocortisone in the studied population may contribute to a better understanding regarding how to administer hydrocortisone and help to inform galenic development. The results in the current thesis therefore represent a first step towards individualising hydrocortisone therapy, which may in the long run contribute to a more rational decision-making in the substitution therapy with hydrocortisone in paediatric patients with adrenal insufficiency.
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