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Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

Katz DA, Liu W, Locke C, Jacobson P, Barnes DM, Basu R, An G, Rieser MJ, Daszkowski D, Groves F, Heneghan G, Shah A, Gevorkyan H, Jhee SS, Ereshefsky L, Marek GJ - Transl Psychiatry (2013)

Bottom Line: Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily.CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites.Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

View Article: PubMed Central - PubMed

Affiliation: AbbVie, North Chicago, IL, USA. david.a.katz@me.com

ABSTRACT
ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

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Related in: MedlinePlus

ABT-384 inhibits its target 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1) in the central nervous system (CNS). Cerebrospinal fluid (CSF) samples were collected hourly during D4 cortisol infusions. D4 cortisol was infused on Day 5 from just after the last dose of ABT-384 for 8 h and again for 8 h starting either 22 (10, 50 mg) or 32 h (1, 2 mg) after the last dose of ABT-384. Subjects who did not receive ABT-384 received only one D4 cortisol infusion. Results are not presented for hour 2 owing to a sample collection problem in one of these two subjects. The median of two individuals is represented for each regimen. See Discussion for potential explanations of negative intrinsic CSF D3 cortisol values.
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fig4: ABT-384 inhibits its target 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1) in the central nervous system (CNS). Cerebrospinal fluid (CSF) samples were collected hourly during D4 cortisol infusions. D4 cortisol was infused on Day 5 from just after the last dose of ABT-384 for 8 h and again for 8 h starting either 22 (10, 50 mg) or 32 h (1, 2 mg) after the last dose of ABT-384. Subjects who did not receive ABT-384 received only one D4 cortisol infusion. Results are not presented for hour 2 owing to a sample collection problem in one of these two subjects. The median of two individuals is represented for each regimen. See Discussion for potential explanations of negative intrinsic CSF D3 cortisol values.

Mentions: Extrinsic and intrinsic CSF D3 cortisol levels were calculated using equations 1 and 2. As many D3CSF.t values were BLQ and the corresponding D3CSF.t,ext values were nonzero, D3CSF.t,int was frequently a negative number. Because of the small number of subjects and high proportion of BLQ values, we did not attempt to establish whether the negative D3CSF.t,int values are distinct from zero. In the results presented here, no attempt was made to impute a nonzero value to BLQ observations of D3CSF.t (Figure 4). A sensitivity analysis was performed in which all BLQ values were assumed to be half the lower limit of quantitation. The results of that analysis were not meaningfully different. The data from subjects to whom ABT-384 was not administered did not clearly establish a steady-state value for intrinsic CSF D3 cortisol. Therefore, any quantitative estimate of CNS HSD-1 inhibition would be speculative. Intrinsic CSF D3 cortisol was positive for the 2, 10 and 50 mg ABT-384 QD regimens at only one time point (for the 10 mg ABT-384 regimen). These data suggest essentially complete CNS HSD-1 inhibition by these regimens. Intrinsic CSF D3 cortisol was positive, yet approximately two- to three-fold lower during hours 4–8 of each infusion, compared with the level attained in the absence of study drug for the 1 mg ABT-384 regimen. These data suggest partial but substantial CNS HSD-1 inhibition, with some diminishment of such inhibition near the end of the second infusion (39–40 h after the last ABT-384 dose).


Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

Katz DA, Liu W, Locke C, Jacobson P, Barnes DM, Basu R, An G, Rieser MJ, Daszkowski D, Groves F, Heneghan G, Shah A, Gevorkyan H, Jhee SS, Ereshefsky L, Marek GJ - Transl Psychiatry (2013)

ABT-384 inhibits its target 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1) in the central nervous system (CNS). Cerebrospinal fluid (CSF) samples were collected hourly during D4 cortisol infusions. D4 cortisol was infused on Day 5 from just after the last dose of ABT-384 for 8 h and again for 8 h starting either 22 (10, 50 mg) or 32 h (1, 2 mg) after the last dose of ABT-384. Subjects who did not receive ABT-384 received only one D4 cortisol infusion. Results are not presented for hour 2 owing to a sample collection problem in one of these two subjects. The median of two individuals is represented for each regimen. See Discussion for potential explanations of negative intrinsic CSF D3 cortisol values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756293&req=5

fig4: ABT-384 inhibits its target 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1) in the central nervous system (CNS). Cerebrospinal fluid (CSF) samples were collected hourly during D4 cortisol infusions. D4 cortisol was infused on Day 5 from just after the last dose of ABT-384 for 8 h and again for 8 h starting either 22 (10, 50 mg) or 32 h (1, 2 mg) after the last dose of ABT-384. Subjects who did not receive ABT-384 received only one D4 cortisol infusion. Results are not presented for hour 2 owing to a sample collection problem in one of these two subjects. The median of two individuals is represented for each regimen. See Discussion for potential explanations of negative intrinsic CSF D3 cortisol values.
Mentions: Extrinsic and intrinsic CSF D3 cortisol levels were calculated using equations 1 and 2. As many D3CSF.t values were BLQ and the corresponding D3CSF.t,ext values were nonzero, D3CSF.t,int was frequently a negative number. Because of the small number of subjects and high proportion of BLQ values, we did not attempt to establish whether the negative D3CSF.t,int values are distinct from zero. In the results presented here, no attempt was made to impute a nonzero value to BLQ observations of D3CSF.t (Figure 4). A sensitivity analysis was performed in which all BLQ values were assumed to be half the lower limit of quantitation. The results of that analysis were not meaningfully different. The data from subjects to whom ABT-384 was not administered did not clearly establish a steady-state value for intrinsic CSF D3 cortisol. Therefore, any quantitative estimate of CNS HSD-1 inhibition would be speculative. Intrinsic CSF D3 cortisol was positive for the 2, 10 and 50 mg ABT-384 QD regimens at only one time point (for the 10 mg ABT-384 regimen). These data suggest essentially complete CNS HSD-1 inhibition by these regimens. Intrinsic CSF D3 cortisol was positive, yet approximately two- to three-fold lower during hours 4–8 of each infusion, compared with the level attained in the absence of study drug for the 1 mg ABT-384 regimen. These data suggest partial but substantial CNS HSD-1 inhibition, with some diminishment of such inhibition near the end of the second infusion (39–40 h after the last ABT-384 dose).

Bottom Line: Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily.CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites.Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

View Article: PubMed Central - PubMed

Affiliation: AbbVie, North Chicago, IL, USA. david.a.katz@me.com

ABSTRACT
ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Show MeSH
Related in: MedlinePlus