Endocrine Abstracts

Introduction: In vitro assessments of osilodrostat (LCI699), a potent oral inhibitor of 11β-hydroxylase suggested potential drug–drug interactions (DDIs) with cytochrome P450 (CYP) enzyme metabolism. This clinical study evaluated the effect of osilodrostat on the pharmacokinetics (PK) of CYP1A2, CYP2C19, CYP2D6, and CYP3A4 probe substrates, caffeine, omeprazole, dextromethorphan, and midazolam, respectively.

Methods: A single-centre, open-label, Phase I, DDI study in healthy adult volunteers (N=20; male/female=10/10). Day 1: A single dose of probe substrates (cocktail approach; caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)) was administered; PK assessments were done over 48 h. Day 2–7: 6-day washout period. Day 8: a single dose of osilodrostat 50 mg was administered followed by a single dose of probe substrates 0.5 h later. PK assessments were conducted over 48 h.

Results: AUC_last geometric mean ratio (GMR) and 90% CI of probe substrate exposure with osilodrostat administration were 2.33 (2.10–2.59), 1.91 (1.74–2.11), 1.48 (1.34–1.63), and 1.50 (1.41–1.60); AUC_∞ GMR (90% CI) were 2.54 (2.34–2.75), 1.86 (1.61–2.15), 1.54 (1.40–1.69), and 1.50 (1.41–1.59) for caffeine, omeprazole, dextromethorphan and midazolam, respectively. C_max GMR (90% CI) for the change in substrate exposure was 1.07 (0.988–1.15), 1.61 (1.40–1.84), 1.35 (1.21–1.50), and 1.47 (1.32–1.62) for caffeine, omeprazole, dextromethorphan and midazolam, respectively. CYP1A2 and CYP2C19 are moderately inhibited and CYP2D6 and CYP3A4 are weakly inhibited by osilodrostat; exposures of probe substrates increased by ~2.5-, ~2.0-, ~1.5-, and ~1.5-fold, respectively.

Conclusions: It is reassuring that CYP3A4 (most clinically important CYP enzyme) was only weakly inhibited by osilodrostat 50 mg single dose, which covers the daily exposure of the maximum dose of 30 mg currently used in clinical trials. In a Phase II study, osilodrostat ≤10 mg twice-daily normalised urinary free cortisol levels in most patients with Cushing’s disease; hence osilodrostat is unlikely to have a clinically relevant impact on the exposures of other medications cleared by CYP3A4.

Disclosure: This work was supported by Novartis.