An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia

Abstract

Aims: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH).

Methods: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an I_max model.

Results: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC₅₀ values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC₅₀ values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively.

Conclusion: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.

Keywords: compartmental analysis; endocrinology; mathematical modelling; paediatric; population pharmacokinetics-pharmacodynamics; steroids.

FIGURE 1

Pharmacokinetic/pharmacodynamic model of cortisol, 17OHP and D4A. The PK are described by a one‐compartment model with first order elimination in which concentration in the central compartment (Cp) is linked to the PD model. Oral hydrocortisone was assumed to enter from a depot compartment using an Erlang absorption model. Endogenous cortisol, 17OHP and D4A were described by indirect response models with zero‐order production and first‐order elimination

FIGURE 2

Spaghetti plot of individual plasma profiles. Lines represent the observed plasma concentrations of cortisol, 17OHP and D4A. Top panel: Cortisol plasma concentrations. Middle panel: 17OHP plasma concentrations. Bottom panel: D4A plasma concentrations

FIGURE 3

IC₅₀ values for cortisol, 17OHP and D4A in SW and SV subjects plotted on a log scale. Left column: IC₅₀ values for cortisol. Middle column: IC₅₀ values for 17OHP. Right column: IC₅₀ values for D4A. Open black circles correspond to the IC₅₀ values for cortisol in subjects with both SW and SV. Open grey circles correspond to the IC₅₀ values for 17OHP and D4A in subjects with SW, and solid grey circles correspond to the median IC₅₀ values. Open orange circles correspond to IC₅₀ values for 17OHP and D4A in subjects with SV, and solid orange circles correspond to the median IC₅₀ values. Dashed lines connect the IC₅₀ values for 17OHP and D4A for each subject, and solid lines connect the median IC₅₀ values

FIGURE 4

Log prediction‐corrected (pc) visual predictive check (pcVPC). Lines represent the 5th, 50th and 95th percentiles of the pc observations; and shaded areas represent 95% prediction intervals of the 5th, 50th and 95th percentiles of pc simulated data. Left panel: Cortisol pcVPC. Middle panel: 17OHP pcVPC. Right panel: D4A pcVPC

FIGURE 5

Observed vs simulated cortisol, 17OHP and D4A 24‐h concentrations for one paediatric patient. The 24‐h concentration–time profiles for cortisol, 17OHP and D4A predicted (solid lines) from the morning dose 6‐h data, along with the observed concentrations (closed circles). Dashed line represents LLOQ. Top panel: Cortisol. Middle panel: 17OHP. Bottom panel: D4A