Healthy
Conditions
Keywords
Tafamidis, B3461103
Brief summary
The purpose of this clinical trial is to compare a tablet and a capsule form of tafamidis without food and to assess the amount of tafamidis in blood after taking the tablet form with food. This study is seeking healthy participants over the age of 18. All participants in the study will receive either one tablet or capsule of study medicine on the first day without food, then receive one dose of the other tablet or capsule form 16 days later without food. All participants will then receive one dose of the tablet form with food 16 days later. We will evaluate the amounts in blood for 8 days after taking each dose of the study medicine. Participants will take part in this study for about 96 days. The first visit is a screening visit to ensure that participants are appropriate for the study. Up to 28 days later, eligible participants will visit the study clinic three times (and stay overnight in the clinical research center for 8 nights each time). The study team will also call participants over the phone 28 to 35 days after the last dose of medicine.
Interventions
12.2 mg tafamidis free acid tablet (Test)
DRUGTafamidis meglumine capsule (Reference)
Commercial 20 mg tafamidis meglumine capsule (Reference)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening. 2. Healthy female participants of nonchildbearing potential and/or male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, and laboratory tests. 3. BMI of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb).
Exclusion criteria
Medical Conditions: 1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). * Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). * History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. * Hypersensitivity to any component of the formulations 2. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions or situations related to COVID-19 pandemic (eg, Contact with positive case, residence, or travel to an area with high incidence) that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Prior/Concomitant Therapy: 3. Use of prescription or nonprescription drugs, dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of study intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional details). 4. Current use of any prohibited concomitant medication(s) or participant unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.9 Prior and Concomitant Therapy. Prior/Concurrent Clinical Study Experience: 5. Previous administration with an investigational product (drug or vaccine) within 6 months (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Diagnostic Assessments: 6. A positive urine drug test. 7. Screening seated BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of seated rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. 8. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF \>450 ms, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT interval is \>450 ms, this interval should be rate-corrected using the Fridericia method only and the resulting QTcF should be used for decision making and reporting. If QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or QRS values used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding a participant. 9. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary: * AST or ALT level ≥ 1.5 × ULN; * Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics(PK) Parameter - Area Under the Concentration-time Curve to Infinity (AUCinf) of PF-06291826 | Predose and 0.5, 1,2,3,4,6,8,12,24 (Day 2),48 (Day 3),72 (Day 4),96 (Day 5),120 (Day 6),144 (Day 7), and 168 (Day 8) hours post dose | AUCinf is defined as area under the concentration-time curve from time 0 to infinity, and calculated by AUC(0-tlast) + (Clast\*/kel), where Clast\* is the estimated plasma concentration at the last quantifiable time point (Clast) estimated form the log-linear regression analysis Clast\* = Clast x e\^(-kel x tlast) |
| PK Parameter - Maximum Observed Concentration (Cmax) of PF-06291826 | Predose and 0.5, 1,2,3,4,6,8,12,24 (Day 2),48 (Day 3),72 (Day 4),96 (Day 5),120 (Day 6),144 (Day 7), and 168 (Day 8) hours post dose | Cmax is defined as maximum observed concentration. |
Countries
Canada
Participant flow
Pre-assignment details
A total of 22 participants were enrolled in this study. Eleven participants were randomized to Sequence 1 and 11 participants were randomized to Sequence 2, all 22 participants received study interventions.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Participants randomized to Sequence 1 received tafamidis free acid tablet 12.2 mg, fasted (Test) in Period 1 followed by commercial tafamidis meglumine soft gelatin capsule 20 mg fasted (Reference) in Period 2 and tafamidis free acid tablet 12.2 mg, fed in Period 3. Each period was separated by a washout of at least 16 days between administration of study drug. | 11 |
| Sequence 2 Participants randomized to Sequence 2 received commercial tafamidis meglumine soft gelatin capsule 20 mg, fasted (Reference) in Period 1 followed by tafamidis free acid tablet 12.2 mg, fasted (Test) in Period 2 and tafamidis free acid tablet 12.2 mg, fed in Period 3. Each period was separated by a washout of at least 16 days between administration of study drug. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 3 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence 1 | Sequence 2 | Total |
|---|---|---|---|
| Age, Continuous | 40.0 Years | 37.0 Years | 39.5 Years |
| Age, Customized 18-25 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 26-35 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Customized 36-45 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized >45 years | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 10 Participants | 21 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 | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 7 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 | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 0 / 21 |
| other Total, other adverse events | 4 / 22 | 2 / 22 | 4 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 21 |
Outcome results
Primary
Pharmacokinetics(PK) Parameter - Area Under the Concentration-time Curve to Infinity (AUCinf) of PF-06291826
AUCinf is defined as area under the concentration-time curve from time 0 to infinity, and calculated by AUC(0-tlast) + (Clast\*/kel), where Clast\* is the estimated plasma concentration at the last quantifiable time point (Clast) estimated form the log-linear regression analysis Clast\* = Clast x e\^(-kel x tlast)
Time frame: Predose and 0.5, 1,2,3,4,6,8,12,24 (Day 2),48 (Day 3),72 (Day 4),96 (Day 5),120 (Day 6),144 (Day 7), and 168 (Day 8) hours post dose
Population: All participants who received at least 1 dose of tafamidis and who had at least 1 of the PK parameters of interest calculated. Here Number of Participants Analyzed signifies participants who contributing to this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tafamidis Free Acid 12.2 mg Oral Tablet (Fasted) | Pharmacokinetics(PK) Parameter - Area Under the Concentration-time Curve to Infinity (AUCinf) of PF-06291826 | 60670 Nanograms * hour per milliliter | Geometric Coefficient of Variation 24 |
| Tafamidis Meglumine 20 mg Oral Capsule (Fasted) | Pharmacokinetics(PK) Parameter - Area Under the Concentration-time Curve to Infinity (AUCinf) of PF-06291826 | 67690 Nanograms * hour per milliliter | Geometric Coefficient of Variation 22 |
| Tafamidis Free Acid 12.2 mg Oral Tablet (Fed) | Pharmacokinetics(PK) Parameter - Area Under the Concentration-time Curve to Infinity (AUCinf) of PF-06291826 | 60210 Nanograms * hour per milliliter | Geometric Coefficient of Variation 28 |
Comparison: Bioequivalence of the Test treatment (Tafamidis free acid 12.2 mg oral tablet \[Fasted\]) to Reference treatment (Tafamidis meglumine 20 mg oral capsule \[Fasted\]) was concluded if the 90% confidence intervals for the ratios of adjusted geometric means for tafamidis AUCinf fell entirely within the acceptance region of (80%,125%).90% CI: [87.1, 99.7]
Primary
PK Parameter - Maximum Observed Concentration (Cmax) of PF-06291826
Cmax is defined as maximum observed concentration.
Time frame: Predose and 0.5, 1,2,3,4,6,8,12,24 (Day 2),48 (Day 3),72 (Day 4),96 (Day 5),120 (Day 6),144 (Day 7), and 168 (Day 8) hours post dose
Population: All participants who received at least 1 dose of tafamidis and who had at least 1 of the PK parameters of interest calculated. Here Number of Participants Analyzed signifies participants who contributing to this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tafamidis Free Acid 12.2 mg Oral Tablet (Fasted) | PK Parameter - Maximum Observed Concentration (Cmax) of PF-06291826 | 1046 Nanograms per milliliter | Geometric Coefficient of Variation 19 |
| Tafamidis Meglumine 20 mg Oral Capsule (Fasted) | PK Parameter - Maximum Observed Concentration (Cmax) of PF-06291826 | 1291 Nanograms per milliliter | Geometric Coefficient of Variation 21 |
| Tafamidis Free Acid 12.2 mg Oral Tablet (Fed) | PK Parameter - Maximum Observed Concentration (Cmax) of PF-06291826 | 891.2 Nanograms per milliliter | Geometric Coefficient of Variation 18 |
Comparison: Bioequivalence of the Test treatment (Tafamidis free acid 12.2 mg oral tablet \[Fasted\]) to Reference treatment (Tafamidis meglumine 20 mg oral capsule \[Fasted\]) was concluded if the 90% confidence intervals for the ratios of adjusted geometric means for tafamidis Cmax fell entirely within the acceptance region of (80%,125%).90% CI: [76.25, 86.04]