Comparison of Steroidogenic Exposure Following the Administration of Repository Corticotropin Injection With a Synthetic ACTH_1‐24 Depot and Methylprednisolone in Healthy Subjects

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of clinically relevant doses of repository corticotropin injection (Acthar Gel) and synthetic ACTH1‐24 depot have not been fully characterized. We compared the steroidogenic exposure of repository corticotropin injection and synthetic ACTH1‐24 depot in healthy adults at therapeutic doses using data from 2 separate phase 1 studies. Subjects were randomly assigned to repository corticotropin injection 40 or 80 IU subcutaneously twice weekly or 80 IU subcutaneously 3 times weekly for 15 days or to daily synthetic ACTH1‐24 depot doses of 0.5 mg subcutaneously, 0.75 mg subcutaneously, 1 mg subcutaneously, or 1 mg intramuscularly for 5 days. A population PK/PD model was developed to simulate the free cortisol exposure of a clinically relevant dose of synthetic ACTH1‐24 depot (1 mg subcutaneously twice weekly). Study drug doses were converted to methylprednisolone‐equivalent doses using the steroidogenic exposure of methylprednisolone 16 mg daily as a conversion factor. Doses were also converted to prednisone equivalents using a coefficient of 1.25. These analyses revealed that the steroidogenic exposure of repository corticotropin injection at clinically relevant doses was substantially lower than that for synthetic ACTH1‐24 depot. The 3 repository corticotropin injection regimens were equivalent to approximately 5, 8, and 16 mg of daily prednisone, respectively. On the basis of simulated free cortisol exposure, synthetic ACTH1‐24 depot 1 mg subcutaneously twice weekly was comparable to 57 mg of daily prednisone. These results suggest that repository corticotropin injection has pharmacological effects that cannot be considered identical to synthetic ACTH1‐24 depot.

Pharmacokinetics and Pharmacodynamics of Repository Corticotropin Injection Compared With Synthetic ACTH1‐24 Depot and Methylprednisolone in Healthy Subjects

“…Synthetic ACTH 1‐24 depot is an investigational drug that is similar to Synacthen Depot, a product used therapeutically in other countries. Results of previous studies have suggested that RCI has less functional activity at MC2R 23 and induces a lower level of endogenous cortisol production than synthetic ACTH 1‐24 depot after a single dose 26,27 . An indirect comparison of 2 independent pharmacokinetic (PK) and pharmacodynamic (PD) studies of RCI and synthetic ACTH 1‐24 depot used a model‐based simulation to compare clinically relevant doses of each drug and found that RCI induced lower cortisol exposure and had a lower steroidogenic exposure than synthetic ACTH 1‐24 depot 27 .…”

Patient-Reported Outcomes from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Repository Corticotropin Injection (Acthar® Gel) for Persistently Active Systemic Lupus Erythematosus

“…These data suggest that RCI may improve SLErelated QoL and impairments beyond the improvements provided by background glucocorticoid and other standard-of-care treatments. Notably, previous studies have demonstrated that RCI induces an endogenous cortisol response that is comparable to low-to-moderate daily glucocorticoid doses [30]; thus, the use of RCI instead of increasing glucocorticoid doses in persistently active disease may be advantageous for reducing steroid exposure while still providing clinical benefit. Additionally, these data suggest that RCI may have greater benefit in patients with higher disease activity.…”

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

“…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 ].…”