Table 2. Open in new tab Efficacy of...

			Basal Condition	ACTH-Stimulated Cortisol, % Change	ACTH-Stimulated Condition
Cortisol-Producing ACA	No. 1	●	0.0519 (0.0296–0.0910)	NT	2.198 (0.375–1.290)	+737	0.0251 (0.00939–0.0700)	NT	0.499 (0.0875–2.851)
No. 2	■	0.206 (0.127–0.333)	0.0632 (0.0541–0.0739)^a	1.392 (0.912–2.127)^a	+538	0.988 (0.641–1.524)	0.440 (0.323–0.600)^b	1.315 (0.753–2.296)
No. 3	◆	0.053 (0.019–0.15)	NT	0.570 (0.13–2.55)^c	NT	NT	NT	NT
No. 4	○	0.044 (0.032–0.059)	NT	NT 0.027 (0.016–0.045)	NT	NT	NT	NT
No. 5	p	0.395 (0.270–0.576)	NT	1.826 (0.551–6.05)^a	NT	NT	NT	NT
No. 6	◇	0.534 (0.360–0.793)	0.412 (0.258–0.667)	2.270 (0.776–6.64)^a	NT	NT	NT	NT
No. 7	▼	0.0217 (0.0102–0.0461)	NT	0.138 (0.0705–0.269)^a	NT	NT	NT	NT
No. 8	▽	NT	0.0226 (0.0164–0.0310)	NT	+207	NT	0.0557 (0.0391–0.0793)	0.0328 (0.0213–0.0504)
ACTH-Dependent Adrenal Hyperplasia	No. 1	●	0.0311 (0.0242–0.0399)	0.105 (0.0658–0.168)^a	0.0702 (0.0423–0.117)^d	+343	0.0887 (0.0371–0.212)	0.138 (0.0644–0.296)	0.138 (0.0578–0.329)
No. 2	■	NT	NT	NT	+127	0.194 (0.118–0.321)	0.263 (0.123–0.533)	0.799 (0.289–1.206)^b
No. 3	◆	0.0232 (0.0146–0.0369)	NT	0.0509 (0.0300–0.0863)^c	NT	NT	NT	NT
ACTH-Independent Adrenal Hyperplasia	No. 1	○	NT	NT	NT	+92	0.0602 (0.0377–0.0960)	NT	0.826 (0.112–6.074)^d
No. 2	p	NT	NT	NT	+48	0.369 (0.224–0.610)	0.430 (0.318–0.581)	1.476 (0.568–3.837)^d
ACC	No. 1	●	0.100 (0.0446–0.226)	NT	0.0728 (0.0376–0.141)	NT	NT	NT	NT
No. 2	p	0.0431 (0.0328–0.0568)	0.0266 (0.0179–0.0396)^c	0.107 (0.0609–0.188)^d	NT	NT	NT	NT

Basal Condition

ACTH-Stimulated Cortisol, % Change

ACTH-Stimulated Condition

Osilodrostat

Metyrapone

Ketoconazole

Osilodrostat

Metyrapone

Ketoconazole

Cortisol-Producing ACA

No. 1

●

0.0519 (0.0296–0.0910)

2.198 (0.375–1.290)

+737

0.0251 (0.00939–0.0700)

0.499 (0.0875–2.851)

No. 2

■

0.206 (0.127–0.333)

0.0632 (0.0541–0.0739)^a

1.392 (0.912–2.127)^a

+538

0.988 (0.641–1.524)

0.440 (0.323–0.600)^b

1.315 (0.753–2.296)

No. 3

◆

0.053 (0.019–0.15)

0.570 (0.13–2.55)^c

No. 4

○

0.044 (0.032–0.059)

NT 0.027 (0.016–0.045)

No. 5

0.395 (0.270–0.576)

1.826 (0.551–6.05)^a

No. 6

◇

0.534 (0.360–0.793)

0.412 (0.258–0.667)

2.270 (0.776–6.64)^a

No. 7

▼

0.0217 (0.0102–0.0461)

0.138 (0.0705–0.269)^a

No. 8

▽

0.0226 (0.0164–0.0310)

+207

0.0557 (0.0391–0.0793)

0.0328 (0.0213–0.0504)

ACTH-Dependent Adrenal Hyperplasia

No. 1

●

0.0311 (0.0242–0.0399)

0.105 (0.0658–0.168)^a

0.0702 (0.0423–0.117)^d

+343

0.0887 (0.0371–0.212)

0.138 (0.0644–0.296)

0.138 (0.0578–0.329)

No. 2

■

+127

0.194 (0.118–0.321)

0.263 (0.123–0.533)

0.799 (0.289–1.206)^b

No. 3

◆

0.0232 (0.0146–0.0369)

0.0509 (0.0300–0.0863)^c

ACTH-Independent Adrenal Hyperplasia

No. 1

○

+92

0.0602 (0.0377–0.0960)

0.826 (0.112–6.074)^d

No. 2

+48

0.369 (0.224–0.610)

0.430 (0.318–0.581)

1.476 (0.568–3.837)^d

ACC

No. 1

●

0.100 (0.0446–0.226)

0.0728 (0.0376–0.141)

No. 2

0.0431 (0.0328–0.0568)

0.0266 (0.0179–0.0396)^c

0.107 (0.0609–0.188)^d

			Basal Condition	ACTH-Stimulated Cortisol, % Change	ACTH-Stimulated Condition
Cortisol-Producing ACA	No. 1	●	0.0519 (0.0296–0.0910)	NT	2.198 (0.375–1.290)	+737	0.0251 (0.00939–0.0700)	NT	0.499 (0.0875–2.851)
No. 2	■	0.206 (0.127–0.333)	0.0632 (0.0541–0.0739)^a	1.392 (0.912–2.127)^a	+538	0.988 (0.641–1.524)	0.440 (0.323–0.600)^b	1.315 (0.753–2.296)
No. 3	◆	0.053 (0.019–0.15)	NT	0.570 (0.13–2.55)^c	NT	NT	NT	NT
No. 4	○	0.044 (0.032–0.059)	NT	NT 0.027 (0.016–0.045)	NT	NT	NT	NT
No. 5	p	0.395 (0.270–0.576)	NT	1.826 (0.551–6.05)^a	NT	NT	NT	NT
No. 6	◇	0.534 (0.360–0.793)	0.412 (0.258–0.667)	2.270 (0.776–6.64)^a	NT	NT	NT	NT
No. 7	▼	0.0217 (0.0102–0.0461)	NT	0.138 (0.0705–0.269)^a	NT	NT	NT	NT
No. 8	▽	NT	0.0226 (0.0164–0.0310)	NT	+207	NT	0.0557 (0.0391–0.0793)	0.0328 (0.0213–0.0504)
ACTH-Dependent Adrenal Hyperplasia	No. 1	●	0.0311 (0.0242–0.0399)	0.105 (0.0658–0.168)^a	0.0702 (0.0423–0.117)^d	+343	0.0887 (0.0371–0.212)	0.138 (0.0644–0.296)	0.138 (0.0578–0.329)
No. 2	■	NT	NT	NT	+127	0.194 (0.118–0.321)	0.263 (0.123–0.533)	0.799 (0.289–1.206)^b
No. 3	◆	0.0232 (0.0146–0.0369)	NT	0.0509 (0.0300–0.0863)^c	NT	NT	NT	NT
ACTH-Independent Adrenal Hyperplasia	No. 1	○	NT	NT	NT	+92	0.0602 (0.0377–0.0960)	NT	0.826 (0.112–6.074)^d
No. 2	p	NT	NT	NT	+48	0.369 (0.224–0.610)	0.430 (0.318–0.581)	1.476 (0.568–3.837)^d
ACC	No. 1	●	0.100 (0.0446–0.226)	NT	0.0728 (0.0376–0.141)	NT	NT	NT	NT
No. 2	p	0.0431 (0.0328–0.0568)	0.0266 (0.0179–0.0396)^c	0.107 (0.0609–0.188)^d	NT	NT	NT	NT

Table 2.

Open in new tab

Efficacy of Osilodrostat, Metyrapone, and Ketoconazole for Cortisol Production by Human Primary Adrenocortical Cultures

			Basal Condition			ACTH-Stimulated Cortisol, % Change	ACTH-Stimulated Condition
			Osilodrostat	Metyrapone	Ketoconazole	ACTH-Stimulated Cortisol, % Change	Osilodrostat	Metyrapone	Ketoconazole
Cortisol-Producing ACA	No. 1	●	0.0519 (0.0296–0.0910)	NT	2.198 (0.375–1.290)	+737	0.0251 (0.00939–0.0700)	NT	0.499 (0.0875–2.851)
	No. 2	■	0.206 (0.127–0.333)	0.0632 (0.0541–0.0739)^a	1.392 (0.912–2.127)^a	+538	0.988 (0.641–1.524)	0.440 (0.323–0.600)^b	1.315 (0.753–2.296)
	No. 3	◆	0.053 (0.019–0.15)	NT	0.570 (0.13–2.55)^c	NT	NT	NT	NT
	No. 4	○	0.044 (0.032–0.059)	NT	NT 0.027 (0.016–0.045)	NT	NT	NT	NT
	No. 5	p	0.395 (0.270–0.576)	NT	1.826 (0.551–6.05)^a	NT	NT	NT	NT
	No. 6	◇	0.534 (0.360–0.793)	0.412 (0.258–0.667)	2.270 (0.776–6.64)^a	NT	NT	NT	NT
	No. 7	▼	0.0217 (0.0102–0.0461)	NT	0.138 (0.0705–0.269)^a	NT	NT	NT	NT
	No. 8	▽	NT	0.0226 (0.0164–0.0310)	NT	+207	NT	0.0557 (0.0391–0.0793)	0.0328 (0.0213–0.0504)
ACTH-Dependent Adrenal Hyperplasia	No. 1	●	0.0311 (0.0242–0.0399)	0.105 (0.0658–0.168)^a	0.0702 (0.0423–0.117)^d	+343	0.0887 (0.0371–0.212)	0.138 (0.0644–0.296)	0.138 (0.0578–0.329)
	No. 2	■	NT	NT	NT	+127	0.194 (0.118–0.321)	0.263 (0.123–0.533)	0.799 (0.289–1.206)^b
	No. 3	◆	0.0232 (0.0146–0.0369)	NT	0.0509 (0.0300–0.0863)^c	NT	NT	NT	NT
ACTH-Independent Adrenal Hyperplasia	No. 1	○	NT	NT	NT	+92	0.0602 (0.0377–0.0960)	NT	0.826 (0.112–6.074)^d
ACTH-Independent Adrenal Hyperplasia	No. 2	p	NT	NT	NT	+48	0.369 (0.224–0.610)	0.430 (0.318–0.581)	1.476 (0.568–3.837)^d
ACC	No. 1	●	0.100 (0.0446–0.226)	NT	0.0728 (0.0376–0.141)	NT	NT	NT	NT
ACC	No. 2	p	0.0431 (0.0328–0.0568)	0.0266 (0.0179–0.0396)^c	0.107 (0.0609–0.188)^d	NT	NT	NT	NT

			Basal Condition			ACTH-Stimulated Cortisol, % Change	ACTH-Stimulated Condition
			Osilodrostat	Metyrapone	Ketoconazole	ACTH-Stimulated Cortisol, % Change	Osilodrostat	Metyrapone	Ketoconazole
Cortisol-Producing ACA	No. 1	●	0.0519 (0.0296–0.0910)	NT	2.198 (0.375–1.290)	+737	0.0251 (0.00939–0.0700)	NT	0.499 (0.0875–2.851)
	No. 2	■	0.206 (0.127–0.333)	0.0632 (0.0541–0.0739)^a	1.392 (0.912–2.127)^a	+538	0.988 (0.641–1.524)	0.440 (0.323–0.600)^b	1.315 (0.753–2.296)
	No. 3	◆	0.053 (0.019–0.15)	NT	0.570 (0.13–2.55)^c	NT	NT	NT	NT
	No. 4	○	0.044 (0.032–0.059)	NT	NT 0.027 (0.016–0.045)	NT	NT	NT	NT
	No. 5	p	0.395 (0.270–0.576)	NT	1.826 (0.551–6.05)^a	NT	NT	NT	NT
	No. 6	◇	0.534 (0.360–0.793)	0.412 (0.258–0.667)	2.270 (0.776–6.64)^a	NT	NT	NT	NT
	No. 7	▼	0.0217 (0.0102–0.0461)	NT	0.138 (0.0705–0.269)^a	NT	NT	NT	NT
	No. 8	▽	NT	0.0226 (0.0164–0.0310)	NT	+207	NT	0.0557 (0.0391–0.0793)	0.0328 (0.0213–0.0504)
ACTH-Dependent Adrenal Hyperplasia	No. 1	●	0.0311 (0.0242–0.0399)	0.105 (0.0658–0.168)^a	0.0702 (0.0423–0.117)^d	+343	0.0887 (0.0371–0.212)	0.138 (0.0644–0.296)	0.138 (0.0578–0.329)
	No. 2	■	NT	NT	NT	+127	0.194 (0.118–0.321)	0.263 (0.123–0.533)	0.799 (0.289–1.206)^b
	No. 3	◆	0.0232 (0.0146–0.0369)	NT	0.0509 (0.0300–0.0863)^c	NT	NT	NT	NT
ACTH-Independent Adrenal Hyperplasia	No. 1	○	NT	NT	NT	+92	0.0602 (0.0377–0.0960)	NT	0.826 (0.112–6.074)^d
ACTH-Independent Adrenal Hyperplasia	No. 2	p	NT	NT	NT	+48	0.369 (0.224–0.610)	0.430 (0.318–0.581)	1.476 (0.568–3.837)^d
ACC	No. 1	●	0.100 (0.0446–0.226)	NT	0.0728 (0.0376–0.141)	NT	NT	NT	NT
ACC	No. 2	p	0.0431 (0.0328–0.0568)	0.0266 (0.0179–0.0396)^c	0.107 (0.0609–0.188)^d	NT	NT	NT	NT

IC50 values are presented in micromolar units. ACTH (85 pM) stimulated cortisol represents the mean percentage increase of cortisol production compared with control, with P < 0.0001 vs control shown in boldface. Column 3 includes the symbols used in Fig. 2 and (26).

Abbreviation: NT, not tested.

P < 0.0001 compared with the IC50 of osilodrostat.

P < 0.001 compared with the IC50 of osilodrostat.

P < 0.05 compared with the IC50 of osilodrostat.

P < 0.01 compared with the IC50 of osilodrostat.

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