ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 GP162 | DOI: 10.1530/endoabs.63.GP162

Pharmacokinetics of osilodrostat following single and multiple doses of osilodrostat in healthy subjects and patients with Cushing's disease

Kevin Han1, Libuse Tauchmanova2, Susan Atkinson2, Christelle Darstein2, Xinrui Zhang1, François Pierre Combes1 & Alberto M Pedroncelli2


1Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 2Novartis Pharma AG, Basel, Switzerland.


Introduction: Osilodrostat is a potent oral 11β-hydroxylase inhibitor currently in Phase III clinical development for the treatment of Cushing’s syndrome (CS). The key pharmacokinetic (PK) properties, drug–drug interactions (DDIs), and population PK findings for osilodrostat in humans are summarized.

Methods: Osilodrostat PK has been characterized in nine Phase I studies (healthy subjects and subjects with hepatic or renal impairment), two Phase II studies (patients with Cushing’s [CD] disease or CS), and a Phase III study (patients with CD). Pooled population PK analyses were performed for healthy subjects and patients with CD.

Results: Osilodrostat was rapidly absorbed (tmax: ~1 h) and demonstrated a half-life of ~4 h across all examined doses (range: 0.5–200 mg after single and multiple doses). Median apparent volume of distribution (Vd) for osilodrostat was 101 L following a single oral dose (50 mg) in healthy volunteers. Osilodrostat is extensively metabolized by multiple enzymes, and no single enzyme contributed to >25% of total clearance of osilodrostat, thus it is unlikely to be a victim for DDIs. The total contributions of cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes to osilodrostat clearance were estimated at 26% and 19%, respectively; non-CYP-, non-UGT-mediated metabolism contributed to ~50% of total clearance. The main metabolite in plasma was LXB168, which is not pharmacologically active. Most osilodrostat-related material was eliminated in urine (~90.6% of administered dose), with only 5.2% as unchanged osilodrostat. Osilodrostat is a moderate inhibitor of CYP1A2, a weak-to-moderate inhibitor of CYP2C19, and a weak inhibitor of CYP2D6 and CYP3A4/5 (50 mg single dose). No clinically significant DDI was observed when osilodrostat was co-administered with oral contraceptives (OCs) in healthy females receiving hydrocortisone. A trend of increasing AUCinf (area under the concentration–time curve from zero to infinity) for osilodrostat was observed in subjects with moderate-to-severe hepatic impairment (geometric mean ratios: 1.44 and 2.66, respectively) compared with healthy subjects. Osilodrostat exposure was similar across three renal function cohorts (normal, severe, and end-stage renal disease), indicating that renal function has no impact on osilodrostat exposure.

Conclusion: The PK properties of osilodrostat in humans are favourable and allow twice-daily dosing. No dose adjustment is required for patients with renal impairment, although patients with moderate or severe hepatic impairment should undergo dose adjustment. Osilodrostat is unlikely to be a victim for DDIs but does produce modest inhibition of CYP enzymes (as perpetrator). OCs can be co-administered with osilodrostat without dose modification.

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