Table 2.

Model parameters for ACTH and cortisol (pharmaco)kinetics after each step of the modeling workflow

Parameter [unit]		Parameter estimates			SIR 95%CI
		Hydrocortisone PK model (Step 1, ABS2)	Endogenous model (Step 2)	Final joint model (Step 3)	Final joint model (Step 3)
ACTH secretion and elimination
SA1 [pmol/h] (70 kg)		-	1160	1300	814–2582
Power BW-SA1‡		-	6.27	6.53	4.80–8.28
SW1 [h]		-	0.659	0.606	0.559–0.651
Pt1 [hh: mm]		-	06:24	06:18	06:06–06:24
SA2 [pmol/h]		-	42.1	50.0	31.7–88.4
SW2 [h]		-	2.74	2.33	1.98–2.66
Pt2 [hh: mm]		-	11:36	11:48	11:18 − 12:06
n		-	4*	4*	-
Kout [1/h]		-	0.698	0.613	0.434–0.819
Base [pmol/L]		-	1.17	1.29	1.14–1.45
IDEX (%)		-	100*	100*	-
ACTH-dependent cortisol production
EC50 [pmol/L]		-	8.85	6.63	5.74–7.94
Emax [nmol/h]		-	7880	5400	4466–6605
γE		-	2.61	2.94	2.74–3.17
Cortisol-dependent ACTH suppression
IC50 [nmol/L]		-	4.70	4.60	4.22–5.06
Imax (%)		-	99.9*	99.9*	-
γI		-	4.62	5.33	4.79–5.95
Hydrocortisone/Cortisol pharmacokinetics
Ka [1/h]		13.6	-	24.0	10.4–120
MTT [h] (5 mg dose)		0.787	-	0.868	0.817–0.925
Power Dose-MTT‡		0.206	-	0.179	0.133–0.219
Ntr		2.13	-	2.12	1.76–2.43
F		0.302	0.302*	0.344	0.298–0.379
CL [L/h] (70 kg) ‡‡		107	107*	106	98.1–113
VC [L] (70 kg) ‡‡		2.03	2.03*	2.15	1.85–2.44
Q [L/h] (70 kg) ‡‡		83.2	83.2*	89.9	75.4–104
Vp [L] (70 kg) ‡‡		54.6	54.6*	61.7	54.9–66.9
NS		4.15*	4.15*	4.15*	-
Kd [nmol/L]		9.71*	9.71*	9.71*	-
Interindividual variability, CV (%)
ω SA1		-	39.9	44.9	31.0-71.7
ω Kout		-	52.8	53.7	40.0-87.1
ω Base		-	24.6	24.6	19.1–32.9
ω EC50		-	26.5	27.6	22.0-38.4
Covariance Base-EC50		-	-	0.0686	0.0384–0.116
ω Ntr		63.7	-	43.0	31.7–63.8
ω F		52.1	-	48.0	37.4–62.3
ω CL		20.9	-	11.4	8.25–15.7
ω Vc		18.3	-	-	-
ω Vp		14.6	-	12.2	9.62–17.3
Interoccasion variability, CV (%)
ω MTT		32.4	-	28.6	24.4–33.8
Residual variability, CV (%)
σ ACTHprop		-	52.9	53.7	51.5–55.2
σ Cortisolprop		31.9	51.5	39.5	38.9–40.1

* Fixed parameters

^‡ Implemented as power covariate model

^‡‡ Theory-based allometric scaling (exponent = 0.75 for flows and = 1 for volumes)

ACTH: Adrenocorticotropic hormone, ALB: Albumin, Base: ACTH baseline concentration, B_max: Maximum binding capacity of CBG, CBG: Corticosteroid binding globulin, BW: Body weight, CL: Clearance, Cortisol_b: Bound cortisol, Cortisol_u: Unbound cortisol, DEX: Dexamethasone, EC₅₀: ACTH concentration yielding half-maximum cortisol production, E_max: Maximum cortisol production rate constant, F: Bioavailability, γE: Hill factor for cortisol production, γI: Hill factor for ACTH suppression, K_a: Absorption rate constant, K_{in, ACTH}: ACTH baseline secretion rate constant, K_d: Dissociation constant cortisol-CBG, K_{out, ACTH}: ACTH elimination rate constant, K_tr: Transit rate constant, IC₅₀: Unbound cortisol concentration yielding half-maximum ACTH suppression, I_DEX: Dexamethasone-driven ACTH suppression, I_max: Maximum ACTH suppression by unbound cortisol, MTT: Mean transit time of oral hydrocortisone, n: Surge functions exponent, N_tr: Number of transit compartments for oral hydrocortisone absorption, NS: Nonspecific binding cortisol-albumin, Pt1: Peak time morning surge, Pt2: Peak time midday surge, Q: Intercompartmental flow, SA1: Amplitude morning surge, SA2: Amplitude midday surge, SW1: Width morning surge, SW2: Width midday surge, T_n: nth transit compartment, V_c: Central volume of distribution, V_p: Peripheral volume of distribution