Wilson Disease
Conditions
Keywords
Cytochrome P450, Healthy, ALXN1840, Celecoxib, CYP2C9
Brief summary
This was a Phase 1, randomized, 2-period, 2-sequence, cross-over study designed to determine the effect of ALXN1840 on the metabolism of celecoxib, a sensitive cytochrome P450 2C9 (CYP2C9) substrate, in healthy male and female participants. The safety and tolerability of ALXN1840 were determined along with ALXN1840 pharmacokinetics (PK) in plasma as measured via total molybdenum with the coadministration of celecoxib.
Detailed description
The study was 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 celecoxib (victim) kinetics in healthy male and female participants. The study had 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 celecoxib, and an End of Study Visit (Day 15 ± 2 days) after Period 2 dosing. Participants only reported to the clinical research unit (CRU) on the day prior to the first dose because they were kept in the CRU during the wash-out period due to coronavirus disease 2019. All participants received a single dose of celecoxib alone (Treatment A) and celecoxib coadministered with ALXN1840 (Treatment B) during the study, 1 in each treatment period. Based on randomization, participants were administered either Treatments A-B or Treatments B-A in each study period. The PK profile of ALXN1840 and celecoxib was determined by blood sampling following single-dose administration. In addition to PK sampling, safety and tolerability were assessed by monitoring adverse events, vital signs, 12-lead electrocardiograms, physical examinations, and laboratory parameters.
Interventions
DRUGALXN1840
ALXN1840 was administered orally as a single dose as 4 x 15 milligram (mg) enteric-coated tablets with 240 milliliters (mL) of water (fasting), for a total dose of 60 mg.
DRUGCelecoxib
Celecoxib was administered orally as a single dose as one 200-mg tablet with 240 mL of water (fasting).
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants were randomized to 1 of 2 treatment sequences: A-B or B-A.
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. * Bodyweight ≥ 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 | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Baseline, up to 336 hours post-dose | Blood samples were collected for pharmacokinetics (PK) analysis of celecoxib. Cmax is reported as nanograms (ng)/milliliter (mL). |
| Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Baseline, up to 336 hours post-dose | Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) is reported as hours•ng/mL (h•ng/mL). |
| Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Baseline, up to 336 hours post-dose | Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) is reported as h•ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax Of Molybdenum With Coadministration Of Celecoxib | Baseline, up to 336 hours post-dose | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and plasma ultrafiltrate (PUF) molybdenum. Cmax is reported as ng/mL. |
| AUCt Of Molybdenum With Coadministration Of Celecoxib | Baseline, up to 336 hours post-dose | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCt is reported as h•ng/mL. |
| AUCinf Of Molybdenum With Coadministration Of Celecoxib | Baseline, up to 336 hours post-dose | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCinf is reported as h•ng/mL. |
Countries
United States
Participant flow
Recruitment details
A total of 70 potential participants were screened for this study, and 36 participants were randomized.
Pre-assignment details
Participants were randomized to 1 of 2 treatment sequences (A-B) or (B-A) in a crossover study design during 2 dosing periods. Participants were scheduled to receive either treatment A or B on Day 1 of each dosing period. There was a washout of at least 14 days between the dosing periods.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence A-B Participants received 1 treatment during each study period in the following sequence:
* Treatment A: Celecoxib.
* Treatment B: Celecoxib plus ALXN1840. | 18 |
| Treatment Sequence B-A Participants received 1 treatment during each study period in the following sequence:
* Treatment B: Celecoxib plus ALXN1840.
* Treatment A: Celecoxib. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 0 | 1 |
| Period 1 | Withdrawal by Subject | 1 | 0 |
| Period 2 | Adverse Event | 0 | 1 |
| Period 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment Sequence A-B | Treatment Sequence B-A | Total |
|---|---|---|---|
| Age, Continuous | 34.5 Years STANDARD_DEVIATION 8.79 | 33.9 Years STANDARD_DEVIATION 7.01 | 34.2 Years STANDARD_DEVIATION 7.84 |
| Body Mass Index | 26.43 Kilograms/squared meter STANDARD_DEVIATION 1.856 | 25.41 Kilograms/squared meter STANDARD_DEVIATION 2.596 | 25.92 Kilograms/squared meter STANDARD_DEVIATION 2.283 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 12 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 170.61 Centimeters STANDARD_DEVIATION 8.225 | 168.21 Centimeters STANDARD_DEVIATION 6.997 | 169.41 Centimeters STANDARD_DEVIATION 7.624 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 7 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
| Weight | 77.29 Kilograms STANDARD_DEVIATION 10.466 | 72.06 Kilograms STANDARD_DEVIATION 9.886 | 74.67 Kilograms STANDARD_DEVIATION 10.378 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 8 / 35 | 3 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 |
Outcome results
Primary
Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) Of Celecoxib With And Without The Coadministration Of ALXN1840
Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) is reported as h•ng/mL.
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 6743 h•ng/mL | Standard Deviation 38 |
| Treatment B | Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 6869 h•ng/mL | Standard Deviation 37.8 |
90% CI: [0.954, 1.07]
Primary
Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) Of Celecoxib With And Without The Coadministration Of ALXN1840
Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) is reported as hours•ng/mL (h•ng/mL).
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 6406 h•ng/mL | Standard Deviation 40.8 |
| Treatment B | Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 6482 h•ng/mL | Standard Deviation 39.9 |
90% CI: [0.959, 1.077]
Primary
Maximum Observed Plasma Concentration (Cmax) Of Celecoxib With And Without The Coadministration Of ALXN1840
Blood samples were collected for pharmacokinetics (PK) analysis of celecoxib. Cmax is reported as nanograms (ng)/milliliter (mL).
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Maximum Observed Plasma Concentration (Cmax) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 637.1 ng/mL | Standard Deviation 48.7 |
| Treatment B | Maximum Observed Plasma Concentration (Cmax) Of Celecoxib With And Without The Coadministration Of ALXN1840 | 567.4 ng/mL | Standard Deviation 49.4 |
90% CI: [0.776, 1.001]
Secondary
AUCinf Of Molybdenum With Coadministration Of Celecoxib
Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCinf is reported as h•ng/mL.
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | AUCinf Of Molybdenum With Coadministration Of Celecoxib | Total Molybdenum | 20910 h•ng/mL | Standard Deviation 47.3 |
| Treatment A | AUCinf Of Molybdenum With Coadministration Of Celecoxib | PUF Molybdenum | 2305 h•ng/mL | Standard Deviation 36.5 |
Secondary
AUCt Of Molybdenum With Coadministration Of Celecoxib
Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCt is reported as h•ng/mL.
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | AUCt Of Molybdenum With Coadministration Of Celecoxib | Total Molybdenum | 19240 h•ng/mL | Standard Deviation 49.1 |
| Treatment A | AUCt Of Molybdenum With Coadministration Of Celecoxib | PUF Molybdenum | 1796 h•ng/mL | Standard Deviation 50.8 |
Secondary
Cmax Of Molybdenum With Coadministration Of Celecoxib
Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and plasma ultrafiltrate (PUF) molybdenum. Cmax is reported as ng/mL.
Time frame: Baseline, up to 336 hours post-dose
Population: Pharmacokinetic Analysis Set: All randomized participants who received both study drugs and had sufficient plasma samples for evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Cmax Of Molybdenum With Coadministration Of Celecoxib | Total Molybdenum | 373.4 ng/mL | Standard Deviation 44.8 |
| Treatment A | Cmax Of Molybdenum With Coadministration Of Celecoxib | PUF Molybdenum | 82.44 ng/mL | Standard Deviation 75.5 |