Healthy Volunteers
Conditions
Brief summary
This study was a non-randomized, open-label, one-sequence, two-period within-subject study to investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy male and female volunteers using itraconazole as a CYP3A inhibitor. The study was conducted at 1 site in the Netherlands.
Interventions
DRUGBalovaptan
In Period 1, balovaptan was administered orally once daily (qd) on Days 1 to 10. In Period 2, balovaptan was administered qd on Days 6 to 20.
DRUGItraconazole
In Period 2, 200 mg itraconzole was administered bid for 4 days and qd on Days 5-20, approximately 12 hours apart. On Days 6-20, 200 mg itraconazole was administered qd.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite | Day 10 of Period 1; Day 10 and Day 15 of Period 2 | — |
| Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan | Day 10 of Period 1, Day 10 and Day 15 of Period 2 | — |
| Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) | Day 10 of Period 1, Day 10 and Day 15 of Period 2 | — |
| Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite | Day 10 of Period 1, Day 10 and Day 15 of Period 2 | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Day 10 of Period 1; Day 10 and Day 15 of Period 2 | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) | Day 10 of Period 1; Day 10 and Day 15 of Period 2 | — |
| Maximum Plasma Concentration (Cmax) for Balovaptan | Day 10 of Period 1, Day 10 and Day 15 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 (as Applicable) | Day 10 of Period 1, Day 10 and Day 15 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, Day 10 and Day 15 of Period 2 | Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. |
Secondary
| Measure | Time frame |
|---|---|
| Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) | Day 10 of Period 1; Day 10 and Day 15 of Period 2 |
| Trough Plasma Concentration (Ctrough) for M3 Metabolite | Day 10 of Period 1; Day 10 and Day 15 of Period 2 |
| Time to Steady State for Balovaptan | Days 1, 3, 5, 8, 9, 10 in Period 1 and Days 1, 3, 5, 8, 9, 10, 13, 14, 15 in Period 2 |
| Percentage of Participants With Adverse Events | Up to 21 days postdose |
| Trough Plasma Concentration (Ctrough) for Balovaptan | Day 10 of Period 1; Day 10 and Day 15 of Period 2 |
Countries
Netherlands
Participant flow
Recruitment details
The study was conducted at 1 site in the Netherlands.
Pre-assignment details
Participants in this study included healthy volunteers.
Participants by arm
| Arm | Count |
|---|---|
| Balovaptan + Itraconzole Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol deviation, pre-existent disease | 1 |
Baseline characteristics
| Characteristic | Balovaptan + Itraconzole |
|---|---|
| Age, Continuous | 43 Years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 12 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 11 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan
Time frame: Day 10 of Period 1, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan | Balovaptan Day 10 of Period 1 | 464 ng.h/mL | Geometric Coefficient of Variation 29.7 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan | Balovaptan + itraconazole Day 10 of Period 2 | 2304 ng.h/mL | Geometric Coefficient of Variation 31.8 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan | Balovaptan + itraconazole Day 15 of Period 2 | 2587 ng.h/mL | Geometric Coefficient of Variation 35.1 |
Primary
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable)
Time frame: Day 10 of Period 1, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) | Balovaptan Day 10 of Period 1 | 230 ng.h/mL | Geometric Coefficient of Variation 26.9 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 10 of Period 2 | 129 ng.h/mL | Geometric Coefficient of Variation 46.9 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 15 of Period 2 | 156 ng.h/mL | Geometric Coefficient of Variation 48.5 |
Primary
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite
Time frame: Day 10 of Period 1, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite | Balovaptan Day 10 of Period 1 | 402 ng.h/mL | Geometric Coefficient of Variation 17.8 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite | Balovaptan + itraconazole Day 10 of Period 2 | 449 ng.h/mL | Geometric Coefficient of Variation 21.3 |
| Balovaptan + Itraconzole | Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite | Balovaptan + itraconazole Day 15 of Period 2 | 570 ng.h/mL | Geometric Coefficient of Variation 20.9 |
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, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Maximum Plasma Concentration (Cmax) for Balovaptan | Balovaptan Day 10 of Period 1 | 31.5 ng/mL | Geometric Coefficient of Variation 25.3 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for Balovaptan | Balovaptan + itraconazole Day 10 of Period 2 | 125 ng/mL | Geometric Coefficient of Variation 27.7 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for Balovaptan | Balovaptan + itraconazole Day 15 of Period 2 | 140 ng/mL | Geometric Coefficient of Variation 31.7 |
Primary
Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable)
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, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) | Balovaptan Day 10 of Period 1 | 11.0 ng/mL | Geometric Coefficient of Variation 26.5 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 10 of Period 2 | 6.34 ng/mL | Geometric Coefficient of Variation 45.3 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 15 of Period 2 | 7.60 ng/mL | Geometric Coefficient of Variation 44.9 |
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, Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Maximum Plasma Concentration (Cmax) for M3 Metabolite | Balovaptan Day 10 of Period 1 | 19.9 ng/mL | Geometric Coefficient of Variation 16.5 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for M3 Metabolite | Balovaptan + itraconazole Day 10 of Period 2 | 21.3 ng/mL | Geometric Coefficient of Variation 20 |
| Balovaptan + Itraconzole | Maximum Plasma Concentration (Cmax) for M3 Metabolite | Balovaptan + itraconazole Day 15 of Period 2 | 28.6 ng/mL | Geometric Coefficient of Variation 19.7 |
Primary
Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Balovaptan Day 10 of Period 1 | 3.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Balovaptan + itraconazole Day 10 of Period 2 | 4.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan | Balovaptan + itraconazole Day 15 of Period 2 | 4.00 Hour(s) |
Primary
Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable)
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) | Balovaptan Day 10 of Period 1 | 5.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 10 of Period 2 | 6.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 15 of Period 2 | 6.00 Hour(s) |
Primary
Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite | Balovaptan Day 10 of Period 1 | 4.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite | Balovaptan + itraconazole Day 10 of Period 2 | 9.00 Hour(s) |
| Balovaptan + Itraconzole | Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite | Balovaptan + itraconazole Day 15 of Period 2 | 3.50 Hour(s) |
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 + Itraconzole | Percentage of Participants With Adverse Events | 73 Percentage |
Secondary
Time to Steady State for Balovaptan
Time frame: Days 1, 3, 5, 8, 9, 10 in Period 1 and Days 1, 3, 5, 8, 9, 10, 13, 14, 15 in Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 (NUMBER) |
|---|---|---|---|
| Balovaptan + Itraconzole | Time to Steady State for Balovaptan | Balovaptan | 4 Day |
| Balovaptan + Itraconzole | Time to Steady State for Balovaptan | Balovaptan + itraconazole | 13 Day |
Secondary
Trough Plasma Concentration (Ctrough) for Balovaptan
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for Balovaptan | Balovaptan Day 10 of Period 1 | 13.3 ng/mL | Standard Deviation 4.7 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for Balovaptan | Balovaptan + itraconazole Day 10 of Period 2 | 91.9 ng/mL | Standard Deviation 26.6 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for Balovaptan | Balovaptan + itraconazole Day 15 of Period 2 | 102 ng/mL | Standard Deviation 36 |
Secondary
Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable)
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) | Balovaptan Day 10 of Period 1 | 9.93 ng/mL | Standard Deviation 2.62 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 10 of Period 2 | 5.82 ng/mL | Standard Deviation 2.99 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) | Balovaptan + itraconazole Day 15 of Period 2 | 6.88 ng/mL | Standard Deviation 3.05 |
Secondary
Trough Plasma Concentration (Ctrough) for M3 Metabolite
Time frame: Day 10 of Period 1; Day 10 and Day 15 of Period 2
Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M3 Metabolite | Balovaptan Day 10 of Period 1 | 15.1 ng/mL | Standard Deviation 2.5 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M3 Metabolite | Balovaptan + itraconazole Day 10 of Period 2 | 18.9 ng/mL | Standard Deviation 4.7 |
| Balovaptan + Itraconzole | Trough Plasma Concentration (Ctrough) for M3 Metabolite | Balovaptan + itraconazole Day 15 of Period 2 | 23.9 ng/mL | Standard Deviation 6.1 |