Three structurally distinct HSD-1 inhibitors have shown tachyphylaxis of pharmacodynamic activity in adipose, a key target tissue, suggesting that the clinical utility of the class might be limited by that pharmacological phenomenon. To determine whether the potent inhibitor clofutriben also showed adipose tachyphylaxis, HSD-1 activity was measured in subcutaneous abdominal adipose of 12 persons with type 2 diabetes and obesity. At steady state, all clofutriben doses were associated with > 90% decreases of mass-labeled cortisol in adipose dialysate with no evidence of tachyphylaxis.

Glucocorticoids effectively treat many diseases, but toxicity limits their utility. We aimed to learn whether, by reducing active intracellular glucocorticoid exposures, the 11β-hydroxysteroid dehydrogenase type 1 inhibitor clofutriben could selectively reduce glucocorticoid efficacy but reduce toxicity more strongly. Further trials to assess clofutriben’s potential to improve the benefit-risk profile of prednisolone are warranted.

11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitors represent a potential therapeutic approach for patients with Cushing’s syndrome, autonomous cortisol secretion (ACS), or iatrogenic glucocorticoid (GC) excess. We assessed whether the HSD-1 inhibitor SPI-62 prevents GC-associated morbidity in a mouse Cushing’s syndrome model.

SPI-62 is a small-molecule HSD-1 inhibitor exhibiting complicated nonlinear pharmacokinetics (PK) in human. The aim of the current analysis was to perform population PK/PD analysis to further link SPI-62 exposure (i.e., PK) with its response (i.e., inhibition of hepatic HSD-1 activity) to gain a quantitative understanding of the SPI-62 dose-exposure-response relationship. A population TMDD-PD model that explains SPI-62 nonlinear PK and hepatic HSD-1 inhibition following different dose regimens in healthy adults was successfully established. Our simulation results provide a solid foundation for model-informed development of SPI-62.

With more potent drug candidates being developed, the incidence of target-mediated drug disposition (TMDD) in small-molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small-molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small-molecule inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) using ABT-384, SPI-62, MK0916, BMS-823778, and BI-187004 as case examples.

SPI-62 is a selective and potent small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). SPI-62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose-dependent volume of distribution, nonlinear PK following the first dose, and dose-proportional PK at steady state, as well as unusually high accumulation ratios at low doses.