Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults

Abstract

Background and ObjectivesOsilodrostat (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.MethodsHealthy 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.ResultsNineteen 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).ConclusionsOsilodrostat 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-017-0497-0) contains supplementary material, which is available to authorized users.

Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail

“…Dextromethorphan plasma AUC ratio and dextromethorphan-to-dextrorphan molar urinary ratio are both often used as markers for CYP2D6 activity in drug interaction studies. 20,21,23,32,33 The dextromethorphan-to-dextrorphan molar urinary ratio was the suggested CYP2D6 activity marker for the Cooperstown 5+1 cocktail. 20 In the current study, the results were consistent between the 2 measures, but slightly more variable for dextromethorphanto-dextrorphan molar urinary ratio than for dextromethorphan plasma AUC ratio (Table 2).…”

Assessment of CYP‐Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans

“…A cocktail approach, involving simultaneous administration of substrates for multiple CYP isozymes to subjects, is effective for evaluation of whether a test drug has the potential for clinically significant DDIs with multiple enzymes. Many cocktail combinations have been reported and their usefulness for DDI evaluation has been proven . However, the use of repaglinide in a cocktail as a substrate for CYP2C8 and the combination of substrates used in this study for several CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A) has not been reported.…”

Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

“…The key question to introspect: would lack of applying specific ADME screens for NASH in adjudicating a drug for clinical development lead to either low/moderate response or therapeutic failure during clinical trials in relevant NASH patients? This question has been asked after rosuvastatin showed poor response in NASH (55). It was reasoned that due to altered transporter related disposition in NASH, the uptake of rosuvastatin into the liver may have been reduced with the concomitant faster basolateral efflux facilitating excretory mechanisms including biliary clearance as qualitatively suggested in the schematic represented in Figure 1 (59-61).…”

“…In this context, we also suggest evaluation whether or not the drug is a perpetrator in NASH patients, using the cocktail approach for CYP enzymes/transporters. Recent literature has provided the impetus for planning and execution of such cocktail probe studies in NASH patients (55)(56)(57).…”