Quantification of tetracosactide (synthetic ACTH) pharmacokinetics and its effects on cortisol production in healthy adults and children
Yersultan Mirasbekov1,2, Davide Bindellini1,2, Charlotte Elder3, Wilhelm Huisinga4, Robin Michelet1, Charlotte Kloft1
1Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 2Graduate Research Training program PharMetrX, 3University of Sheffield, 4Institute of Mathematics, University of Potsdam
Introduction and Objectives Congenital adrenal hyperplasia patients exhibit cortisol deficiency and often require lifelong cortisol replacement therapy. To optimise this therapy, a better understanding of the cortisol-producing system in the healthy state is needed. The short Synacthen test (SST) is a diagnostic tool to assess adrenal function [1,2]. In brief, synthetic ACTH is administered and cortisol production response is measured. Tetracosactide, or Synacthen®, is one of these shorter synthetic analogues of endogenous ACTH, stimulating cortisol production in the adrenal glands [1,3]. Doses used in SST are subdivided into low and high dose tests (LDT and HDT), corresponding to an intravenous (i.v.) bolus of 1 µg and 250 µg (145 µg/m² for children) [1,3]. In order to improve our understanding of the endogenous cortisol production in adults and children, the aim of this work was to leverage SST data to investigate tetracosactide pharmacokinetics and its effect on cortisol production, to evaluate a previously developed ACTH-cortisol dynamics model and to evaluate its applicability to the paediatric population [4,5]. Methods Clinical trial data were collected from 36 healthy adults (19-46 years) and 24 healthy children (5-14 years) receiving dexamethasone to suppress endogenous ACTH and cortisol production [6]. Plasma ACTH and plasma cortisol concentrations were measured following LDT (23 adults, 12 children) or HDT (12 adults, 12 children). Tetracosactide baseline values were estimated using pre-dose observations from 1-6 visits, and the M3 method was applied to handle BLQ measurements [6-8]. A baseline adjustment method was applied to account for endogenous ACTH and interfering substrates detected by immunoassays [1,7]. Different structural PK models were assessed with linear or nonlinear elimination via Michaelis-Menten kinetics. Theory-based allometric scaling was evaluated to characterise PK differences between adults and paediatrics [8-10]. Inclusion of IIV was evaluated on all structural parameters. Additive, exponential and combined RUV models in the log-transformed domain were tested. Nested and non-nested models were compared based on the difference in OFV or AIC, respectively. Models were evaluated based on parameter plausibility, the precision of estimates and GOF plots. PD modelling of cortisol response was performed by joining knowledge about baseline, production and disposition processes. Baseline cortisol amount was modelled by initialising the cortisol central compartment using pre-dose observations [11]. ACTH-dependent cortisol production was based on a previously developed model for ACTH-cortisol dynamics using a sigmoidal Emax model [4]. Based on the same model, cortisol disposition was characterised by a two-compartment model, theory-based allometric scaling and a plasma protein binding model [4,5]. The PD modelling of tetracosactide, using fixed individual PK parameter values, allowed evaluation of the previously developed ACTH-cortisol dynamics model in adults and paediatrics. Results Based on pre-dose observations from several visits (N=309, 51% BLQ), the typical estimate for ACTH baseline was 17.2 pmol/L (with 68.6% CV IIV). Using baseline adjusted PK modelling, tetracosactide concentration-time profiles were best described by a two-compartment model with linear elimination and theory-based allometric scaling. Parameter estimates were as follows: CL=17.9 L/h (with 68.3% CV IIV), Vc=0.19 L, Q=3.73 L/h and Vp=0.5 L. Parameters were precisely estimated (RSE of 3-28%), and GOF plots showed that individual predictions had good agreement with observed data. The distribution density for empirical Bayes estimates on CL did not show any major differences between adults and children; however, it showed a trend between LDT and HDT groups, suggesting potential dose dependencies. Evaluation of the PD model demonstrated an acceptable prediction of the plasma cortisol concentration for healthy adults. Results from the paediatric population showed overprediction of cortisol concentrations. Re-estimation of maximum cortisol production rate constant (Emax parameter) showed a change from 5400 nmol/h to 3720 nmol/h and 3050 nmol/h for adult and paediatric populations, respectively. Conclusion A PK/PD model of tetracosactide was developed to describe concentration-time profiles of plasma tetracosactide and plasma cortisol. The developed model provides first insights regarding the mechanism of cortisol production, and it showed promising potential to further elucidate differences in cortisol production processes between adults and children.
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