Chemical formula: C₁₃H₁₀FN₃ Molecular mass: 227.242 g/mol PubChem compound: 44139752
Osilodrostat is a cortisol synthesis inhibitor. It potently inhibits 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.
CYP11B1 inhibition is associated with the accumulation of precursors such as 11-deoxycortisol and acceleration of adrenal biosynthesis including androgens. In Cushing’s disease, the fall in plasma cortisol concentration also stimulates ACTH secretion, via the feedback mechanism which accelerates steroid biosynthesis.
In a thorough QT study (n=86 male and female healthy volunteers) with osilodrostat, the maximum QTcF interval duration differences to placebo were 1.73 ms (90% CI: 0.15, 3.31) at the 10 mg dose and 25.38 ms (90% CI: 23.53, 27.22) at a supratherapeutic dose of 150 mg. Based on an interpolation of these results, the mean maximum prolongation at the highest recommended dose of 30 mg is estimated to be +5.3 ms.
Osilodrostat is a highly soluble, highly permeable compound (BCS class 1). It is rapidly absorbed (tmax ~1 h) and oral absorption in humans is assumed to be nearly complete. Steady state is reached by day 2.
Co-administration with food did not affect absorption to a clinically significant extent. In a healthy volunteer study (n=20), the administration of a single dose of 30 mg osilodrostat with a high-fat meal resulted in a modest reduction of AUC and Cmax by 11% and 21%, respectively, and the median tmax was delayed from 1 to 2.5 hours.
No clinically relevant accumulation was observed in clinical studies. An accumulation ratio of 1.3 was estimated for the 2 to 30 mg dose range.
The median apparent volume of distribution (Vz/F) of osilodrostat is approximately 100 litres. Protein binding of osilodrostat and of its major metabolite M34.5 is low (less than 40%) and concentration-independent. The osilodrostat blood-to-plasma concentration ratio is 0.85. Osilodrostat is not a substrate for OATP1B1 or OATP1B3 transporters.
In a human ADME study in healthy subjects following the administration of a single dose of 50 mg [14C]-osilodrostat, metabolism was deemed the most important clearance pathway for osilodrostat since ~80% of the dose was excreted as metabolites. The three main metabolites in plasma (M34.5, M16.5 and M24.9) represented 51%, 9% and 7% of the dose, respectively. Both M34.5 and M24.9 have longer half-lives than osilodrostat and some accumulation is expected with twice-daily dosing. The decrease in the contribution of osilodrostat to the radioactivity AUC with time post-dose was found to coincide closely with a corresponding increase in the contribution of M34.5.
Thirteen metabolites were characterised in the urine, with the three main metabolites being M16.5, M22 (an M34.5 glucuronide) and M24.9, with 17, 13 and 11% of the dose, respectively. The formation of the major urinary metabolite M16.5 (direct N-glucuronide) was catalysed by UGT1A4, 2B7 and 2B10. Less than 1% of the dose was excreted as M34.5 (di-oxygenated osilodrostat) in the urine but 13% of the dose was identified as M22 (M34.5-glucuronide). The formation of M34.5 was non-CYP-mediated.
Multiple CYP enzymes and UDP glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes more than 25% to the total clearance. The main CYP enzymes involved in osilodrostat metabolism are CYP3A4, 2B6 and 2D6. Total CYP contribution is 26%, total UGT contribution is 19% and non-CYP non-UGT mediated metabolism was shown to contribute to ~50% of total clearance. In addition, osilodrostat showed a high intrinsic permeability, low efflux ratio and modest impact of inhibitors on the efflux ratio in vitro. This suggests that the potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low.
In vitro data indicate that the metabolites do not contribute to the pharmacological effect of osilodrostat.
The elimination half-life of osilodrostat is approximately 4 hours. In an ADME study, the majority (91%) of the radioactive dose of osilodrostat was eliminated in the urine, with only a minor amount eliminated in the faeces (1.6% of dose). The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.
Exposure (AUCinf and Cmax) increased more than dose-proportionally over the therapeutic dose range.
In vitro data indicate that neither osilodrostat nor its major metabolite M34.5 inhibits the following enzymes and transporters at clinically relevant concentrations: CYP2A6, CYP2C8, CYP2C9, UGT2B7, P-gp, BCRP, BSEP, MRP2, OATP1B3 and MATE2-K. Since the exposure of M34.5 has not yet been determined after repeated dosing, the clinical relevance of the in vitro drug-drug interaction results for M34.5 is unknown.
In a phase I study in 33 subjects with varying degrees of hepatic function using a single dose of 30 mg osilodrostat, AUCinf was 1.4- and 2.7-fold higher in the moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment cohorts, respectively. Cmax was 15 and 20% lower in the moderate and severe cohorts. The terminal half-life increased to 9.3 hours and 19.5 hours in the moderate and severe cohorts. Mild hepatic impairment (Child-Pugh A) did not influence exposure to any significant extent. The absorption rate was not affected by the degree of hepatic impairment.
In a phase I study in 15 subjects with varying degrees of renal function using a single dose of 30 mg osilodrostat, comparable systemic exposure was seen in subjects with severe renal impairment, end-stage renal disease and normal renal function.
The relative bioavailability was approximately 20% higher in Asian patients compared to other ethnicities. Body weight was not shown to be a major determinant of this difference.
Age and gender had no significant impact on osilodrostat exposure in adults. The number of elderly patients in clinical studies was limited.
In repeat dose toxicity studies conducted in mice, rats and dogs, the central nervous system, liver, female reproductive organs, and the adrenal gland were the primary target organs. The NOAEL for hepatic, reproductive organ and adrenal effects in long-term (26- and 39-week) studies was at least four-fold human clinical exposure based on AUC. CNS findings (aggression, hypersensitivity to touch and increased or decreased activity) were noted in the rat, mouse and dog. The NOAEL for the CNS effects was approximately 2-fold human free Cmax based on the most sensitive species.
Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation do not indicate a relevant risk in humans. In rat and mice carcinogenicity studies, an increased incidence of hepatocellular adenoma/carcinoma (at lower doses in males than females), and neoplastic changes of thyroid follicular adenoma/carcinoma (in male rats only) were observed. The findings are likely rodent specific and considered not relevant to humans.
Reproductive studies in rabbits and rats demonstrated embryotoxicity, foetotoxicity (increased resorptions and decreased foetal viability, decreased foetal weights, external malformations, and visceral and skeletal variations) and teratogenicity at maternally toxic doses. The NOAEL was 10-fold human exposure (AUC) in a pre- and postnatal developmental study, and 8- to 73-fold human exposure (AUC) in a rat fertility and early embryonic development study. The maternal and foetal NOAEL in the rabbit embryofoetal development study was 0.6-fold human exposure (AUC).
The findings in juvenile rat toxicity studies were largely consistent with those observed in adult rat studies. Delayed sexual maturation was noted at high doses with no effects on overall reproductive performance or parameters after a 6-week recovery period. There were no effects on long bone growth or behavioural performance.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
