Healthy Volunteers
Conditions
Brief summary
This study was a single-center, non-randomized, open-label, one-sequence, two-period, within-subject study to investigate the effects of multiple doses of rifampicin on the PK and safety of multiple doses of balovaptan in healthy subjects. The study was conducted at 1 site in the Netherlands.
Interventions
DRUGBalovaptan
In Period 1, balovaptan was administered alone as a once daily (qd) dose on Days 1 to 10. In Period 2, balovaptan was administered as a qd dose on Days 7 to 16.
DRUGRifampicin
In Period 2, 600 mg of rifampicin will be administered alone as a qd dose from Day 1 to Day 6, and as a qd dose on Days 7 to 16.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female subjects. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, urinalysis, and serology. * Body Mass Index of 18 to 30 kg/m2, inclusive. * For women of childbearing potential: agreement to use at least 2 acceptable contraceptive methods during the treatment period and for 90 days after the last dose of study drug. * For men: agreement to use contraceptive measures, and agreement to refrain from donating sperm until 90 days after the last dose of study drug.
Exclusion criteria
* Female subjects who are pregnant or lactating. * Any condition or disease detected during the medical interview/physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator. Rifampicin-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) for Balovaptan | Day 10 of Period 1 and Day 16 of Period 2 | Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. |
| Maximum Plasma Concentration (Cmax) for M2 Metabolite | Day 10 of Period 1 and Day 16 of Period 2 | Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. |
| Maximum Plasma Concentration (Cmax) for M3 Metabolite | Day 10 of Period 1 and Day 16 of Period 2 | Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. |
| Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan | Day 10 and 11 of Period 1; Day 16 and 17 of Period 2 | AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose. |
| Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite | Day 10 and 11 of Period 1; Day 16 and 17 of Period 2 | AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose. |
| Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite | Day 10 and 11 of Period 1; Day 16 and 17 of Period 2 | AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24 | Day 10 and 11 of Period 1; Day 16 and 17 of Period 2 | — |
| Percentage of Participants With Adverse Events | Up to 21 days postdose | — |
| Metabolite to Parent Ratio for M3 Metabolite Based on Cmax | Day 10 of Period 1 and Day 16 of Period 2 | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Day 10 of Period 1 and Day 16 of Period 2 | Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units. |
| Time to Maximum Observed Plasma Concentration for M2 Metabolite | Day 10 of Period 1 and Day 16 of Period 2 | Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units. |
| Time to Maximum Observed Plasma Concentration for M3 Metabolite | Day 10 of Period 1 and Day 16 of Period 2 | Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units. |
| Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24 | Day 10 and 11 of Period 1; Day 16 and 17 of Period 2 | — |
| Metabolite to Parent Ratio for M2 Metabolite Based on Cmax | Day 10 of Period 1 and Day 16 of Period 2 | — |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Balovaptan + Rifampicin Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Balovaptan + Rifampicin |
|---|---|
| Age, Continuous | 39.0 Years STANDARD_DEVIATION 14.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 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 | 0 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 | 16 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 15 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan
AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time frame: Day 10 and 11 of Period 1; Day 16 and 17 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan | Balovaptan (Period 1) | 1000 ng.h/mL | Geometric Coefficient of Variation 29.6 |
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan | Balovaptan + rifampicin (Period 2) | 67.0 ng.h/mL | Geometric Coefficient of Variation 16.3 |
Primary
Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite
AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time frame: Day 10 and 11 of Period 1; Day 16 and 17 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite | Balovaptan (Period 1) | 448 ng.h/mL | Geometric Coefficient of Variation 22.7 |
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite | Balovaptan + rifampicin (Period 2) | 149 ng.h/mL | Geometric Coefficient of Variation 21.9 |
Primary
Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite
AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time frame: Day 10 and 11 of Period 1; Day 16 and 17 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite | Balovaptan (Period 1) | 844 ng.h/mL | Geometric Coefficient of Variation 20.8 |
| Balovaptan + Rifampicin | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite | Balovaptan + rifampicin (Period 2) | 110 ng.h/mL | Geometric Coefficient of Variation 13.3 |
Primary
Maximum Plasma Concentration (Cmax) for Balovaptan
Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for Balovaptan | Balovaptan (Period 1) | 94.2 ng/mL | Geometric Coefficient of Variation 33.4 |
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for Balovaptan | Balovaptan + rifampicin (Period 2) | 12.9 ng/mL | Geometric Coefficient of Variation 22.8 |
Primary
Maximum Plasma Concentration (Cmax) for M2 Metabolite
Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for M2 Metabolite | Balovaptan (Period 1) | 22.0 ng/mL | Geometric Coefficient of Variation 22.7 |
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for M2 Metabolite | Balovaptan + rifampicin (Period 2) | 8.09 ng/mL | Geometric Coefficient of Variation 20.5 |
Primary
Maximum Plasma Concentration (Cmax) for M3 Metabolite
Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for M3 Metabolite | Balovaptan (Period 1) | 49.6 ng/mL | Geometric Coefficient of Variation 26.4 |
| Balovaptan + Rifampicin | Maximum Plasma Concentration (Cmax) for M3 Metabolite | Balovaptan + rifampicin (Period 2) | 10.9 ng/mL | Geometric Coefficient of Variation 23.2 |
Secondary
Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24
Time frame: Day 10 and 11 of Period 1; Day 16 and 17 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24 | Balovaptan (Period 1) | 0.430 Ratio | Geometric Coefficient of Variation 32.3 |
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24 | Balovaptan + rifampicin (Period 2) | 2.14 Ratio | Geometric Coefficient of Variation 14.8 |
Secondary
Metabolite to Parent Ratio for M2 Metabolite Based on Cmax
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M2 Metabolite Based on Cmax | Balovaptan (Period 1) | 0.225 Ratio | Geometric Coefficient of Variation 30.9 |
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M2 Metabolite Based on Cmax | Balovaptan + rifampicin (Period 2) | 0.606 Ratio | Geometric Coefficient of Variation 20.7 |
Secondary
Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24
Time frame: Day 10 and 11 of Period 1; Day 16 and 17 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24 | Balovaptan + rifampicin (Period 2) | 1.70 Ratio | Geometric Coefficient of Variation 6.9 |
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24 | Balovaptan (Period 1) | 0.872 Ratio | Geometric Coefficient of Variation 16.6 |
Secondary
Metabolite to Parent Ratio for M3 Metabolite Based on Cmax
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M3 Metabolite Based on Cmax | Balovaptan (Period 1) | 0.545 Ratio | Geometric Coefficient of Variation 16.5 |
| Balovaptan + Rifampicin | Metabolite to Parent Ratio for M3 Metabolite Based on Cmax | Balovaptan + rifampicin (Period 2) | 0.873 Ratio | Geometric Coefficient of Variation 9 |
Secondary
Percentage of Participants With Adverse Events
Time frame: Up to 21 days postdose
Population: The safety analysis population consisted of subjects who received at least one dose of balovaptan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Balovaptan + Rifampicin | Percentage of Participants With Adverse Events | 94 Percentage |
Secondary
Time to Maximum Observed Plasma Concentration for M2 Metabolite
Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration for M2 Metabolite | Balovaptan (Period 1) | 2.50 Hours |
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration for M2 Metabolite | Balovaptan + rifampicin (Period 2) | 3.00 Hours |
Secondary
Time to Maximum Observed Plasma Concentration for M3 Metabolite
Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration for M3 Metabolite | Balovaptan (Period 1) | 1.00 Hour(s) |
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration for M3 Metabolite | Balovaptan + rifampicin (Period 2) | 1.00 Hour(s) |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan
Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time frame: Day 10 of Period 1 and Day 16 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Balovaptan (Period 1) | 1.00 Hour |
| Balovaptan + Rifampicin | Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Balovaptan + rifampicin (Period 2) | 1.00 Hour |