Pharmacokinetics and Pharmacodynamics of Repository Corticotropin Injection Compared With Synthetic ACTH_1‐24 Depot and Methylprednisolone in Healthy Subjects

Abstract

Repository corticotropin injection (RCI; Acthar Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides. This phase 1, single-center, open-label, randomized parallel study directly compared the pharmacokinetics and pharmacodynamics of RCI and synthetic ACTH 1-24 depot. Methylprednisolone was included to estimate the steroidogenic exposure of RCI and synthetic ACTH 1-24 depot when used to treat nephrotic syndrome. A total of 48 healthy subjects aged 18 to 50 years were randomly assigned 1:1:1 to RCI (80 IU subcutaneously twice weekly on study days 1 and 4), synthetic ACTH 1-24 depot (1 mg subcutaneously twice weekly on study days 1 and 4), or methylprednisolone (32 mg orally once daily on study days 1 through 6). After 2 doses, RCI induced about 5-fold lower free cortisol exposure and an estimated 4-fold lower steroidogenic exposure than synthetic ACTH 1-24 depot. The lower endogenous cortisol response of RCI was achieved despite higher observed mean plasma concentrations of N25-deamidated porcine ACTH 1-39 (the pharmacokinetic marker for RCI) than of ACTH 1-24 . The different pharmacodynamic properties demonstrated by RCI and synthetic ACTH 1-24 depot in this study suggest that these products in the ACTH class are not interchangeable.

Repository Corticotropin Injection for the Treatment of Pulmonary Sarcoidosis: A Narrative Review

“…These side effects are consistent with those seen with glucocorticoids [61]; this may be expected considering that endogenous production of cortisol from the adrenal cortex is one of the mechanisms of RCI, albeit at lower levels than observed with other MCR agonists [31]. However, RCI is multi-mechanistic in that it may also cause direct modulation of immune cells, such as B cells and macrophages, independently of steroids [28,31]. This is supported by a recent systematic review showing distinct AE profiles between RCI and glucocorticoids in the treatment of rheumatoid arthritis [64].…”

“…Possible side effects of RCI may include change in glucose tolerance, hypertension, and increased appetite and weight gain [ 60 , 61 , 63 ]. These side effects are consistent with those seen with glucocorticoids [ 61 ]; this may be expected considering that endogenous production of cortisol from the adrenal cortex is one of the mechanisms of RCI, albeit at lower levels than observed with other MCR agonists [ 31 ]. However, RCI is multi-mechanistic in that it may also cause direct modulation of immune cells, such as B cells and macrophages, independently of steroids [ 28 , 31 ].…”

“…However, in animal studies, RCI induced significantly lower corticosterone levels than synthetic ACTH 1–24 , consistent with their respective functional activity at MC2R [ 28 ]. Pharmacologic studies in healthy human subjects have also demonstrated that RCI induces lower cortisol production than does synthetic ACTH 1–24 depot at clinically relevant doses, further supporting that RCI has a unique mechanism of action [ 30 , 31 ]. The lower cortisol response of RCI was achieved despite plasma concentrations of the pharmacokinetic marker of RCI (N25-deamidated porcine ACTH 1–39 ) being higher than concentrations of ACTH 1–24 [ 31 ].…”

A Narrative Review of Repository Corticotropin Injection for the Treatment of Systemic Lupus Erythematosus

“…The anti-inflammatory mechanism of action for RCI was originally thought to be via activation of MC2R on adrenocortical cells, which stimulates production of endogenous cortisol; however, recent evidence has shown that RCI has relatively low agonistic activity of MC2R [ 20 , 21 ]. This is supported by studies in animals [ 20 ] and healthy human subjects [ 21 , 22 ], which showed lower levels of endogenous corticosteroid production after administration of RCI compared to synthetic ACTH 1–24 (Fig. 1 ).…”

“…ACTH 1–24 first 24 amino acids of adrenocorticotropic hormone, RCI repository corticotropin injection, SEM standard error of the mean. Reproduced from Poola et al [ 22 ] under the CC BY-NC-ND 4.0 open access license …”