Healthy
Conditions
Brief summary
The main purpose of this study is to evaluate the effect of imlunestrant (LY3484356) when administered orally on the levels of midazolam in the blood stream in healthy women of non-childbearing potential. The study will also evaluate the safety and tolerability of imlunestrant in healthy women of non-childbearing potential. This study will last up to approximately 6 weeks for each participant including the screening period.
Interventions
DRUGMidazolam
Administered orally.
DRUGImlunestrant
Administered orally.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
This is a fixed sequence, crossover study
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Women not of childbearing potential * Participants who are overtly healthy as determined by medical assessment * Participants with body mass index (BMI) of 18.0 and 35.0 kilograms per meter squared (kg/m²), inclusive
Exclusion criteria
* Have known allergies to imlunestrant, related compounds or any components of the formulation or midazolam * Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder * Use or intend to use medications that are substrate drugs of P-glycoprotein
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) of Midazolam | Day 1: Predose, 0.25hours (h), 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose | PK: AUC\[0-∞\] of Midazolam |
| PK: Maximum Observed Concentration (Cmax) of Midazolam | Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose | PK: Cmax of Midazolam |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK: AUC[0-∞] of 1'-Hydroxymidazolam | Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose | PK: AUC\[0-∞\] of 1'-hydroxymidazolam |
| PK: Cmax of 1'-Hydroxymidazolam | Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose | PK: Cmax of 1'-hydroxymidazolam |
| PK: Area Under the Concentration Versus Time Curve From Zero to 24 Hours at Steady State (AUC[0-24], ss) of Imlunestrant When Dosed in the Presence of Midazolam | Day 9: Predose, 0.25 h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose | PK: AUC\[0-24\], ss of Imlunestrant |
| PK: Maximum Observed Concentration at Steady State (Cmax, ss) of Imlunestrant When Dosed in the Presence of Midazolam | Day 9: Predose, 0.25 h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose | PK: Cmax, ss of Imlunestrant when dosed in the presence of Midazolam is evaluated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Midazolam + Imlunestrant Participants received 400 mg Imlunestrant (2 × 200 mg) tablets administered QD orally for 7 days on Days 3 to 9 and a single 0.5 mg midazolam solution orally on Day 1 and Day 9 as per below dosing sequence:
Day 1: 0.5 mg midazolam alone
Days 3 to 8: 400 mg imlunestrant QD alone
Day 9: 0.5 mg midazolam + 400 mg imlunestrant
There was a washout period of 8 days between doses of midazolam. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Midazolam + Imlunestrant |
|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 5 / 20 | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) of Midazolam
PK: AUC\[0-∞\] of Midazolam
Time frame: Day 1: Predose, 0.25hours (h), 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose
Population: All participants who received at least one dose of study drug (midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) of Midazolam | 12.3 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 32 |
| 0.5 mg Midazolam + 400 mg Imlunestrant | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) of Midazolam | 11.4 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 41 |
Comparison: A mixed effects model was used to estimate drug-drug interaction using the Model: Log(PK) = Treatment + Participant + Random Error, where Participant is fitted as a random effect.90% CI: [0.849, 1.02]Mixed Models Analysis
Primary
PK: Maximum Observed Concentration (Cmax) of Midazolam
PK: Cmax of Midazolam
Time frame: Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose
Population: All participants who received at least one dose of study drug (midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | PK: Maximum Observed Concentration (Cmax) of Midazolam | 3.84 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
| 0.5 mg Midazolam + 400 mg Imlunestrant | PK: Maximum Observed Concentration (Cmax) of Midazolam | 4.12 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 31 |
Comparison: A mixed effects model was used to estimate drug-drug interaction using the Model: Log(PK) = Treatment + Participant + Random Error, where Participant is fitted as a random effect.90% CI: [0.989, 1.16]Mixed Models Analysis
Secondary
PK: Area Under the Concentration Versus Time Curve From Zero to 24 Hours at Steady State (AUC[0-24], ss) of Imlunestrant When Dosed in the Presence of Midazolam
PK: AUC\[0-24\], ss of Imlunestrant
Time frame: Day 9: Predose, 0.25 h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose
Population: All participants who received at least one dose of study drug (imlunestrant or midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | PK: Area Under the Concentration Versus Time Curve From Zero to 24 Hours at Steady State (AUC[0-24], ss) of Imlunestrant When Dosed in the Presence of Midazolam | 2020 ng*hr/mL | Geometric Coefficient of Variation 53 |
Secondary
PK: AUC[0-∞] of 1'-Hydroxymidazolam
PK: AUC\[0-∞\] of 1'-hydroxymidazolam
Time frame: Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose
Population: All participants who received at least one dose of study drug (midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | PK: AUC[0-∞] of 1'-Hydroxymidazolam | 2.75 ng*hr/mL | Geometric Coefficient of Variation 40 |
| 0.5 mg Midazolam + 400 mg Imlunestrant | PK: AUC[0-∞] of 1'-Hydroxymidazolam | 2.26 ng*hr/mL | Geometric Coefficient of Variation 40 |
Comparison: A mixed effects model was used to estimate drug-drug interaction using the Model: Log(PK) = Treatment + Participant + Random Error, where Participant is fitted as a random effect.90% CI: [0.777, 0.868]Mixed Models Analysis
Secondary
PK: Cmax of 1'-Hydroxymidazolam
PK: Cmax of 1'-hydroxymidazolam
Time frame: Day 1: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose; Day 9: Predose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24, 36, 48h postdose
Population: All participants who received at least one dose of study drug (midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | PK: Cmax of 1'-Hydroxymidazolam | 0.748 ng/mL | Geometric Coefficient of Variation 40 |
| 0.5 mg Midazolam + 400 mg Imlunestrant | PK: Cmax of 1'-Hydroxymidazolam | 0.722 ng/mL | Geometric Coefficient of Variation 35 |
Comparison: A mixed effects model was used to estimate drug-drug interaction using the Model: Log(PK) = Treatment + Participant + Random Error, where Participant is fitted as a random effect.90% CI: [0.828, 1.12]Mixed Models Analysis
Secondary
PK: Maximum Observed Concentration at Steady State (Cmax, ss) of Imlunestrant When Dosed in the Presence of Midazolam
PK: Cmax, ss of Imlunestrant when dosed in the presence of Midazolam is evaluated.
Time frame: Day 9: Predose, 0.25 h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h postdose
Population: All participants who received at least one dose of study drug (imlunestrant or midazolam) and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Midazolam | PK: Maximum Observed Concentration at Steady State (Cmax, ss) of Imlunestrant When Dosed in the Presence of Midazolam | 120 ng/mL | Geometric Coefficient of Variation 51 |