Healthy Volunteers
Conditions
Brief summary
The main purpose of this study is to look at the effect of ketoconazole and fluconazole on how much baricitinib gets into the blood stream. The study will also look at the tolerability of baricitinib and ketoconazole when given together and the tolerability of baricitinib and fluconazole when given together. Participants will be recruited into 1 of 2 treatment groups (Group A or Group B). Each treatment group will participate in 2 study periods. Participants will take baricitinib alone in 1 period and baricitinib with either ketoconazole or fluconazole in the other period. This study will last approximately 7 weeks.
Interventions
DRUGBaricitinib
Administered orally
DRUGKetoconazole
Administered orally
DRUGFluconazole
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Overtly healthy as determined by medical history and physical examination * Female participants not of childbearing potential due to surgical sterilization (at least 3 months after surgical hysterectomy, bilateral oophorectomy with or without hysterectomy, or bilateral tubal occlusion/ligation) confirmed by medical history or menopause * Have a body mass index of 18 to 29 kilograms per square meter (kg/m\^2), inclusive, at screening
Exclusion criteria
* Participants who have previously completed or withdrawn from this study or any other study investigating baricitinib, and have previously received the study drug * Have known allergies to baricitinib, ketoconazole, fluconazole, related compounds, or any components of the baricitinib, ketoconazole, or fluconazole formulations, or history of significant atopy * Have a history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data * Have a current or recent history \[less than 30 days prior to screening and/or less than 45 days prior to day of admission to Clinical Research Unit (CRU)\] of a clinically significant bacterial, fungal, parasitic, viral (not including rhinopharyngitis), or mycobacterial infection * Have alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, or gamma glutamyl transferase (GGT) values above the upper limit of the reference range for the local laboratory at screening or day of admission to CRU * Have an absolute neutrophil count (ANC) less than 2 times 10\^9 per liter (L) \[2000 cells per microliter (μL)\] at screening or day of admission to CRU. For abnormal values, a single repeat will be allowed * Intend to use over-the-counter or prescription medication and/or herbal supplements within 14 days prior to dosing and during the study (with the exception of occasional paracetamol, which will be permitted at the discretion of the investigator), or intended use of vitamin supplements from Day 1 until discharge from the CRU * Have used or intend to use any drugs or substances that are known to be substrates, inhibitors, or inducers of cytochrome P450 (CYP) 3A4, CYP2C9, or CYP2C19 within 30 days prior to dosing and throughout the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
| PK: AUC(0-∞) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
| PK: Maximum Concentration (Cmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
| PK: Cmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
| PK: Time of Maximum Observed Drug Concentration (Tmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
| PK: Tmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose |
Countries
United Kingdom
Participant flow
Pre-assignment details
This was an open-label, 2-period, fixed-sequence study. Period 1 was from Day 1 through Day 2. Period 2 was from Day 3 through Day 9 for baricitinib + ketoconazole (Group A) and Day 3 through Day 10 for baricitinib + fluconazole (Group B).
Participants by arm
| Arm | Count |
|---|---|
| Baricitinib + Ketoconazole (Group A) 10 mg baricitinib administered orally once on Day 1 of Period 1 and on Day 6 of Period 2.
400 mg Ketoconazole administered orally QD for 6 days (Day 3 through Day 8) in Period 2. | 18 |
| Baricitinib + Fluconazole (Group B) 10 mg baricitinib administered orally once on Day 1 of Period 1 and on Day 7 of Period 2.
400 mg fluconazole administered orally once on Day 3 of Period 2, followed by 200 mg administered orally QD for 6 days (Day 4 through Day 9) in Period 2. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 | Adverse Event | 0 | 1 |
| Period 2 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Baricitinib + Ketoconazole (Group A) | Total | Baricitinib + Fluconazole (Group B) |
|---|---|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 15 | 42.5 years STANDARD_DEVIATION 14.2 | 42.7 years STANDARD_DEVIATION 13.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 36 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 32 Participants | 16 Participants |
| Region of Enrollment United Kingdom | 18 Participants | 36 Participants | 18 Participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 16 Participants | 28 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 18 | 7 / 18 | 4 / 17 | 3 / 18 | 4 / 18 | 6 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 17 | 0 / 18 | 0 / 18 | 0 / 17 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole
Time frame: Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + ketoconazole in Period 2) and had PK data to calculate AUC(0-∞) of baricitinib.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baricitinib (Group A) | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 720 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 23 |
| Baricitinib + Ketoconazole (Group A) | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 868 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
Primary
PK: AUC(0-∞) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole
Time frame: Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + fluconazole in Period 2) and had PK data to calculate AUC(0-∞) of baricitinib.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baricitinib (Group A) | PK: AUC(0-∞) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 698 ng*h/mL | Geometric Coefficient of Variation 24 |
| Baricitinib + Ketoconazole (Group A) | PK: AUC(0-∞) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 851 ng*h/mL | Geometric Coefficient of Variation 24 |
Primary
PK: Cmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole
Time frame: Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + fluconazole in Period 2) and had PK data to calculate Cmax of baricitinib.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baricitinib (Group A) | PK: Cmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 103 ng/mL | Geometric Coefficient of Variation 36 |
| Baricitinib + Ketoconazole (Group A) | PK: Cmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 107 ng/mL | Geometric Coefficient of Variation 38 |
Primary
PK: Maximum Concentration (Cmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole
Time frame: Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + ketoconazole in Period 2) and had PK data to calculate Cmax of baricitinib.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baricitinib (Group A) | PK: Maximum Concentration (Cmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 106 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 27 |
| Baricitinib + Ketoconazole (Group A) | PK: Maximum Concentration (Cmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 115 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 32 |
Primary
PK: Time of Maximum Observed Drug Concentration (Tmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole
Time frame: Days 1 and 6: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + ketoconazole in Period 2) and had PK data to calculate Tmax of baricitinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baricitinib (Group A) | PK: Time of Maximum Observed Drug Concentration (Tmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 1.00 hours |
| Baricitinib + Ketoconazole (Group A) | PK: Time of Maximum Observed Drug Concentration (Tmax) of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Ketoconazole | 1.00 hours |
Primary
PK: Tmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole
Time frame: Days 1 and 7: predose of baricitinib and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 and 48 hours postdose
Population: All enrolled participants who received study drug (baricitinib in Period 1 and baricitinib + fluconazole in Period 2) and had PK data to calculate Tmax of baricitinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baricitinib (Group A) | PK: Tmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 1.00 hours |
| Baricitinib + Ketoconazole (Group A) | PK: Tmax of Baricitinib Following Single Doses of Baricitinib Alone or Coadministered With Fluconazole | 1.00 hours |