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

This was a single-center, phase I, open-label, fixed-sequence, DDI study in healthy adult volunteers: male and female individuals aged between 18 and 55 years with systolic and diastolic blood pressure, pulse rate, and body temperature within normal ranges, body weight between 50 and 100 kg, and body mass index between 18 and 33 kg/m² were recruited. Subjects were excluded from the study if they had used or consumed substances known to interfere with those CYP enzymes being investigated.

The study consisted of two treatment periods. In period 1 (day 1), each subject received a single dose of the probe drug cocktail (modified Cooperstown cocktail) orally, which contained caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg). After a washout period of 6 days, in period 2 (day 8), subjects received a single 50-mg dose of osilodrostat orally followed by a single dose of probe drug cocktail 30 min later. Blood samples were collected after administration of the cocktail in both study periods at the following time points: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 h post-dose. Plasma concentrations of the cocktail probe substrates were assayed using validated methods (WuXi AppTec Co., Ltd). The analytes were extracted from plasma samples and analysis was performed by validated liquid chromatography-tandem mass spectrometry assay. The limits of quantitation for the different analytes were 25.0 ng/mL for caffeine, 0.1 ng/mL for dextromethorphan, 3.0 ng/mL for omeprazole, 0.05 ng/mL for midazolam, and 1.0 ng/mL for osilodrostat. Plasma concentrations of osilodrostat were assayed using a validated liquid chromatography-tandem mass spectrometry assay, with a limit of quantitation of 1.00 ng/mL [10].

The safety set included all subjects who received at least one dose of study medication. Five separate pharmacokinetic analysis sets were evaluated, one for each probe drug substrate and one for osilodrostat. For each probe substrate, the pharmacokinetic analysis set included all subjects who received the planned amount of probe substrate in period 1 or the planned amount of probe substrate plus osilodrostat in period 2, did not vomit within 4 h of study drug administration, and had sufficient pharmacokinetic concentration data to determine at least one evaluable primary pharmacokinetic parameter. The pharmacokinetic analysis set for osilodrostat included all subjects who received the planned amount of osilodrostat in period 2, did not vomit within 4 h of study drug administration, and had at least one evaluable pharmacokinetic parameter.

The primary objective was to assess the effect of osilodrostat on the pharmacokinetic parameters of the CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 probe substrates caffeine, omeprazole, dextromethorphan, and midazolam using a modified Cooperstown cocktail in healthy adult subjects. Secondary objectives included: determination of key pharmacokinetic parameters [area under the concentration-time curve (AUC) from time zero to the last measureable concentration (AUC_last), AUC from time zero extrapolated to infinity (AUC_inf), and maximum plasma concentration (C _max)] for metabolites of the probe substrates [i.e., paraxanthine (caffeine), dextrorphan (dextromethorphan), 5-hydroxyomeprazole (omeprazole), and hydroxymidazolam (midazolam)]; pharmacokinetic exposure of a single 50-mg dose of osilodrostat; and safety and tolerability of osilodrostat when co-administered with probe substrates. All pharmacokinetic parameters of osilodrostat and cocktail probe substrates were determined by non-compartmental analysis using Phoenix WinNonlin version 6.2.

Statistical analyses of the pharmacokinetic parameters for the primary objective were performed using the pharmacokinetic analysis set for each probe drug. The single-dose pharmacokinetics of each of the probe drugs administered with and without a single 50-mg dose of osilodrostat was compared using a model-based statistical analysis. The single-dose pharmacokinetic parameters AUC_last, AUC_inf, and C _max for the CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 substrates (caffeine, dextromethorphan, omeprazole, and midazolam) were log transformed and analyzed separately for each probe drug with a linear mixed-effects model. For the DDI analysis, the point estimate for the treatment difference in least-squares means (for the log pharmacokinetic parameters) and the corresponding 90% confidence intervals (CIs) were calculated to obtain the point estimate and 90% CI for the ratio of geometric means (for the pharmacokinetic parameters) of the test compared with the reference [(probe plus osilodrostat 50 mg)/probe alone]. The 90% CIs for the ratio of geometric means for AUC_last, AUC_inf, and C _max of substrates with and without osilodrostat co-administration were determined. Descriptive statistics were reported for all secondary pharmacokinetic analyses.

A physiologically based pharmacokinetic (PBPK) model was developed for osilodrostat within the framework of the Simcyp^® Simulator (version 15, release 1; Certara Inc.). The model incorporated physiochemical and clinical pharmacokinetic parameters, in vitro and in vivo enzyme phenotyping information, and in vitro CYP perpetrator (inhibition and induction) characteristics of osilodrostat. The Supplemental Information contains details of the methods and results from the in vitro CYP inhibition (Supplemental Table 1), CYP induction (Supplemental Tables 2 and 3), CYP enzyme reaction phenotyping studies (Supplemental Table 4), and the input parameters for the PBPK model (Supplemental Table 5). The model was developed to simulate the concentration-time profiles and pharmacokinetic parameters of osilodrostat after 30- and 50-mg single doses. In addition, the model was developed to simulate the pharmacokinetic parameters and the geometric mean AUC and C _max ratios of the CYP probe substrates when co-administered with a single 50-mg dose of osilodrostat according to the actual clinical trial design described above. The qualified model was then used to predict the pharmacokinetics of osilodrostat after multiple 30-mg twice-daily doses (14 days), and to predict the DDIs of the CYP probe substrates dosed on day 14 after multiple doses of osilodrostat (30 mg twice daily, dosed on days 1–16).

Twenty subjects entered the study, of whom 19 completed it (one subject discontinued the study because of withdrawal of consent). The median age was 41.5 years (range 27–55 years); most subjects (95%) were Caucasian, ten subjects were male, and the mean (standard deviation) body mass index and weight were 24.4 (2.9) kg/m² and 73.0 (12.9) kg, respectively.

Co-administration of each probe substrate with a single 50-mg dose of osilodrostat resulted in a modest increase in exposure vs. probe substrate alone (Fig. 1). When caffeine was co-administered with osilodrostat, higher caffeine concentrations were observed vs. caffeine alone (Fig. 2a). Although large variations were observed at each time point for both omeprazole and dextromethorphan when co-administered with osilodrostat, there was an overall increase in omeprazole and dextromethorphan exposures (Fig. 2b, c, respectively). Midazolam co-administered with osilodrostat produced a slight increase in midazolam exposure compared with midazolam alone (Fig. 2d). The increased exposure of caffeine, omeprazole, dextromethorphan, and midazolam following co-administration with osilodrostat indicated a modest inhibitory effect of osilodrostat on each probe substrate (Table 1).

Caffeine, omeprazole, and midazolam were eliminated more slowly when co-administered with osilodrostat vs. alone, as indicated by a longer half-life and a 61, 30, and 33% decrease in apparent total clearance of the drug from plasma after oral administration, respectively (Table 1). Dextromethorphan data for these parameters were affected by large inter-patient variations (data not shown), mainly owing to two outliers with extreme values, consistent with subjects who are poor metabolizers of dextromethorphan.

There was a reduction in metabolite formation of all four probe substrates following co-administration of osilodrostat compared with administration of the probe substrates alone. Caffeine, omeprazole, dextromethorphan, and midazolam metabolite ratios were reduced by 62, 21, 35, and 14%, respectively.

Following a single oral dose of osilodrostat 50 mg, peak plasma concentration occurred at ~1.53 h. The geometric mean (coefficient of variation) of AUC_inf and C _max was 3430 ng·h/mL (30.2%) and 392 ng/mL (21.4%), respectively, with a half-life of 4.73 h.

All 20 subjects were included in the safety analysis set. Of these, at least one AE was experienced by eight subjects (40%). AEs suspected to be drug related were reported by six subjects (30%); fatigue (three subjects; 15%) and dizziness (two subjects; 10%) were most common, with one subject reporting flatulence and diarrhea (5%). These AEs resolved on the day of onset (except flatulence, which resolved on the next day after onset) without any action. All but one of the suspected AEs were of grade 1 severity; one AE of dizziness was of grade 2 severity. No grade 3 or 4 AEs, or serious AEs, were reported.

The PBPK model was qualified to simulate the concentration-time profiles and pharmacokinetic parameters of osilodrostat 30- and 50-mg single oral doses (Supplemental Fig. 1 and Supplemental Table 6). The PBPK-modeled pharmacokinetic parameters were within 15% of the observed values. This model was further qualified to simulate the DDI of a single 50-mg osilodrostat dose on the individual CYP probe substrates according to the actual trial design. The model simulated the geometric mean AUC ratios within 30% of the observed value for all CYP substrates (Table 2). With this qualified model, osilodrostat (30 mg twice daily) concentration-time profile and pharmacokinetic parameters were predicted up to 14 days of dosing (Supplemental Fig. 2 and Supplemental Table 6). After multiple 30-mg twice-daily doses of osilodrostat (days 1−16) with a single dose of CYP substrates on day 14, the model predicted a similar DDI effect to that with a single 50-mg dose of osilodrostat for the CYP1A2, CYP2D6, and CYP3A4/5 substrates (≤3% change; Table 2). For CYP2C19, a modest increase of 26% in the geometric mean AUC ratio was predicted after 30 mg twice-daily multiple osilodrostat doses compared with a single 50-mg dose. This predicted increase after multiple osilodrostat doses was a result of the additional time-dependent nature of CYP2C19 inhibition by osilodrostat.