Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults.
OBJECTIVE
Osilodrostat (LCI699) is an adrenal steroidogenesis inhibitor currently in late-phase clinical development as a potential treatment for Cushing's disease. This study evaluated the inhibitory effect of osilodrostat on the pharmacokinetics of probe substrates of the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4.


METHODS
Healthy adult volunteers received single-dose cocktail probe substrates [caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)] followed by a 6-day washout. Subjects then received a single dose of osilodrostat 50 mg followed by a single dose of cocktail probe substrates.


RESULTS
Nineteen of twenty subjects (ten were male) completed the study. Mean age, body weight, and body mass index were 41.8 years, 73.0 kg, and 24.4 kg/m2. Geometric mean ratio of the area under the concentration-time curve from time zero to the last measureable concentration and 90% confidence intervals of probe substrate exposure with osilodrostat were: caffeine (CYP1A2 probe substrate), 2.33 (2.10-2.59); omeprazole (CYP2C19), 1.91 (1.74-2.11); dextromethorphan (CYP2D6), 1.48 (1.34-1.63); and midazolam (CYP3A4/5), 1.50 (1.41-1.60). Corresponding values for geometric mean ratio of maximum plasma concentration (90% confidence interval) for the change in substrate exposure were 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).


CONCLUSIONS
Osilodrostat is a moderate inhibitor of CYP1A2 and CYP2C19 and a weak inhibitor of CYP2D6 and the most clinically important CYP enzyme, CYP3A4. Osilodrostat is unlikely to significantly increase the exposures of other medications cleared by CYP3A4. These findings are clinically relevant given that Cushing's disease is a chronic condition often requiring multiple medications and that most other therapies have significant drug interaction potential.
PAREXEL International GmbH, Berlin, Germany.
Sara
S
Armani
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.|Currently at Merck & Co., Rahway, NJ, USA.
Lillian
L
Ting
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Nicholas
N
Sauter
Novartis Pharma AG, Basel, Switzerland.
Christelle
C
Darstein
Novartis Healthcare Pvt. Ltd, Hyderabad, India.|Currently at PAREXEL International Pvt. Ltd, Hyderabad, India.
Anadya Prakash
AP
Tripathi
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Lai
L
Wang
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Bing
B
Zhu
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Helen
H
Gu
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Dung Yu
DY
Chun
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.
Heidi J
HJ
Einolf
Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA. swarupa.kulkarni@novartis.com.
Swarupa
S
Kulkarni
D000328:Adult; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007093:Imidazoles; D011725:Pyridines; D002110:Caffeine; C553306:Osilodrostat; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D009853:Omeprazole; D008874:Midazolam