Wilson Disease
Conditions
Keywords
Cytochrome P450, Healthy, ALXN1840
Brief summary
This is a Phase 1, randomized, 2-period, 2-sequence, cross-over study designed to determine the effect of ALXN1840 on the metabolism of bupropion, a sensitive cytochrome P450 2B6 (CYP2B6) substrate, in healthy male and female participants. The safety and tolerability of ALXN1840 will be determined along with ALXN1840 pharmacokinetics (PK) in plasma as measured via total molybdenum with the coadministration of bupropion.
Detailed description
The study is being conducted as a randomized, 2-period, 2-sequence, cross-over study to determine the effect of a single dose of ALXN1840 (perpetrator) on the single-dose bupropion (victim) kinetics in healthy male and female participants. The study has a Screening Period (Day -28 to Day -2), two 11-day study periods (Day 1 to Day 11) with a minimum of 14 days between doses of bupropion, and an End of Study Visit (Day 15 ± 2 days) after Period 2 dosing. Participants will report to the clinical research unit on the day prior (Day -1) to both dosing periods. All participants will receive 1 treatment in each study period; treatment order will be defined based on randomization: Treatments A and B. The time between dosing bupropion alone or in combination with ALXN1840 in each treatment sequence will be a minimum of 14 days. The PK profile of ALXN1840 and bupropion will be determined by blood sampling following single dose administration.
Interventions
DRUGALXN1840
ALXN1840 will be administered orally as a single dose as 4 x 15 mg enteric-coated tablets with 240 milliliters of water (fasting), for a total dose of 60 mg.
Bupropion hydrochloride will be administered orally as a single dose as one 150 milligrams (mg) tablet with 240 milliliters of water (fasting).
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Adequate venous access in the left or right arm to allow the collection of blood samples. * Body weight ≥ 45 to ≤ 100 kilograms (kg) and body mass index within the range of 18 to \< 30 kg/meter squared. * Willing and able to follow protocol-specified contraception requirements. * Capable of giving signed informed consent.
Exclusion criteria
* History or presence of/significant medical history. * Clinically significant multiple or severe allergies. * Lymphoma, leukemia, or any malignancy within 5 years. * Breast cancer within the past 10 years. * Serum creatinine \> upper limit of normal (ULN) of the reference range. * Alanine aminotransferase, aspartate aminotransferase, or total bilirubin \> ULN. * Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * QTc \> 450 milliseconds (msec) for male participants or \> 470 msec for female participants.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Bupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUCt) of Bupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUCinf) of Bupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Plasma Total Molybdenum With Coadministration of Bupropion | Pre-dose (Day 1) up to 336 hours post-dose | Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only. |
| AUCt of Plasma Total Molybdenum With Coadministration of Bupropion | Pre-dose (Day 1) up to 336 hours post-dose | Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only. |
| Cmax of Hydroxybupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose | — |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 up to Day 15 | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with the study drug and which did not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A TEAE was defined as any AE that began or worsened on or after the first dose of treatment until the end of study (EOS) or early termination (ET). An AE that occurred during the washout period between drugs was considered treatment emergent to the last drug given. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| AUCinf of Plasma Total Molybdenum With Coadministration of Bupropion | Pre-dose (Day 1) up to 336 hours post-dose | Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only. |
| AUCt of Hydroxybupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose | — |
| AUCinf of Hydroxybupropion With and Without the Coadministration of ALXN1840 | Pre-dose (Day 1) up to 336 hours post-dose | — |
Countries
United States
Participant flow
Pre-assignment details
Eligible participants were randomized to 1 of the two treatment sequences (A-B or B-A) on Day 1 prior to dosing in Period 1. Participants were scheduled to receive a single treatment (A or B) on Day 1 of each treatment period in the crossover design.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence A-B Participants received a single oral dose of 1 × 150 mg bupropion HCl salt tablet in a fasted state on Day 1 of treatment period 1. Treatment B: Participants received a single oral dose of 1 × 150 mg bupropion HCl salt tablet coadministered with 4 × 15 mg EC tablets of ALXN1840 in a fasted state on Day 1 of treatment period 2. There was a washout period of 14 days between the 2 treatment periods. | 27 |
| Treatment Sequence B-A Treatment B: Participants received a single oral dose of 1 × 150 mg bupropion HCl salt tablet coadministered with 4 × 15 mg EC tablets of ALXN1840 in a fasted state on Day 1 of treatment period 1. Treatment A: Participants received a single oral dose of 1 × 150 mg bupropion HCl salt tablet in a fasted state on Day 1 of treatment period 2. There was a washout period of 14 days between the 2 treatment periods. | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor decision | 7 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Treatment Sequence B-A | Total | Treatment Sequence A-B |
|---|---|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 9.22 | 32.3 years STANDARD_DEVIATION 8.9 | 31.6 years STANDARD_DEVIATION 8.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 20 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 34 Participants | 15 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 | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 14 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 20 Participants | 37 Participants | 17 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 19 Participants | 38 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 8 / 50 | 11 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUCinf) of Bupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUCinf) of Bupropion With and Without the Coadministration of ALXN1840 | 1049 hours*ng/mL | Geometric Coefficient of Variation 32.9 |
| Treatment B: Bupropion HCl + ALXN1840 | Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUCinf) of Bupropion With and Without the Coadministration of ALXN1840 | 1039 hours*ng/mL | Geometric Coefficient of Variation 31.3 |
90% CI: [0.9368, 1.0269]
Primary
Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUCt) of Bupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUCt) of Bupropion With and Without the Coadministration of ALXN1840 | 1021 hours*ng/mL | Geometric Coefficient of Variation 33.4 |
| Treatment B: Bupropion HCl + ALXN1840 | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUCt) of Bupropion With and Without the Coadministration of ALXN1840 | 1010 hours*ng/mL | Geometric Coefficient of Variation 31.6 |
90% CI: [0.9344, 1.0244]
Primary
Maximum Observed Plasma Concentration (Cmax) of Bupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | Maximum Observed Plasma Concentration (Cmax) of Bupropion With and Without the Coadministration of ALXN1840 | 98.64 nanograms (ng)/milliliter (mL) | Geometric Coefficient of Variation 31.6 |
| Treatment B: Bupropion HCl + ALXN1840 | Maximum Observed Plasma Concentration (Cmax) of Bupropion With and Without the Coadministration of ALXN1840 | 98.02 nanograms (ng)/milliliter (mL) | Geometric Coefficient of Variation 27.9 |
90% CI: [0.9415, 1.0205]
Secondary
AUCinf of Hydroxybupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | AUCinf of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 11960 hours*ng/mL | Geometric Coefficient of Variation 59.5 |
| Treatment B: Bupropion HCl + ALXN1840 | AUCinf of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 11630 hours*ng/mL | Geometric Coefficient of Variation 54.8 |
Secondary
AUCinf of Plasma Total Molybdenum With Coadministration of Bupropion
Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only.
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | AUCinf of Plasma Total Molybdenum With Coadministration of Bupropion | 16130 hours*ng/mL | Geometric Coefficient of Variation 65.9 |
Secondary
AUCt of Hydroxybupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | AUCt of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 11900 hours*ng/mL | Geometric Coefficient of Variation 60.2 |
| Treatment B: Bupropion HCl + ALXN1840 | AUCt of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 11560 hours*ng/mL | Geometric Coefficient of Variation 55.3 |
Secondary
AUCt of Plasma Total Molybdenum With Coadministration of Bupropion
Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only.
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | AUCt of Plasma Total Molybdenum With Coadministration of Bupropion | 15010 hours*ng/mL | Geometric Coefficient of Variation 68.1 |
Secondary
Cmax of Hydroxybupropion With and Without the Coadministration of ALXN1840
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | Cmax of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 286.5 ng/mL | Geometric Coefficient of Variation 53.8 |
| Treatment B: Bupropion HCl + ALXN1840 | Cmax of Hydroxybupropion With and Without the Coadministration of ALXN1840 | 284.3 ng/mL | Geometric Coefficient of Variation 53.6 |
Secondary
Cmax of Plasma Total Molybdenum With Coadministration of Bupropion
Plasma total molybdenum was assessed as surrogate measures for ALXN1840 PK following coadministration with bupropion HCl salt tablet (Treatment B) only.
Time frame: Pre-dose (Day 1) up to 336 hours post-dose
Population: PK analysis set included all participants who had sufficient plasma samples to have evaluable PK data for bupropion and/or total molybdenum (as a measure of ALXN1840) in plasma. Here, 'overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Bupropion HCl | Cmax of Plasma Total Molybdenum With Coadministration of Bupropion | 325.6 ng/mL | Geometric Coefficient of Variation 51.1 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with the study drug and which did not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A TEAE was defined as any AE that began or worsened on or after the first dose of treatment until the end of study (EOS) or early termination (ET). An AE that occurred during the washout period between drugs was considered treatment emergent to the last drug given. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Day 1 up to Day 15
Population: Safety set included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment A: Bupropion HCl | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 8 participants |
| Treatment B: Bupropion HCl + ALXN1840 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 11 participants |