Hypercholesterolemia
Conditions
Keywords
Bioqeuivalence, Pharmacokinetics, Atorvastatin
Brief summary
To determine whether new 80 mg atorvastatin tablets are bioequivalent to 80 mg commercial atorvastatin tablets (Lipitor®).
Interventions
DRUGAtorvastatin
A single 80 mg dose of marketed 80 mg atorvastatin tablets
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female subjects between the ages of 18 and 55 years. * Body Mass Index (BMI) of 18 to 30 kg/m2; and a total body weight \>50 kg (110 lbs).
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) disease or clinical findings at screening. * Treatment with an investigational drug within 30 days or 5 half lives preceding the first dose of study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity) | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose | AUCinf = Area under the plasma concentration-time curve from time 0 (predose) extrapolated to infinite time; measured in nanograms times hour per milliliter (ng\*hr/mL). Pharmacokinetic (PK) parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose | AUClast = area under the plasma concentration-time curve from 0 (predose) to the time of the last measureable concentration (Clast). PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4. |
| Maximum Observed Plasma Concentration (Cmax) | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose | Cmax = maximum observed plasma concentration. Measured in nanograms per milliter (ng/mL); collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose | Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence; PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4. |
| Plasma Elimination Half-life (t1/2) | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose | t1/2 = terminal elimination half-life in hours; ln 2/kel, where kel is the termination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total Study Population New 80 milligram (mg) atorvastatin tablets (test); marketed 80 mg atorvastatin commercial tablet (Lipitor®) (reference) | 76 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2: Second Intervention | family emergency | 1 | 0 |
| Period: Washout Period of > = 2 Weeks | Protocol Violation | 1 | 0 |
| Period: Washout Period of > = 2 Weeks | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total Study Population |
|---|---|
| Age, Continuous | 41.0 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 76 | 4 / 74 |
| serious Total, serious adverse events | 0 / 76 | 0 / 74 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity)
AUCinf = Area under the plasma concentration-time curve from time 0 (predose) extrapolated to infinite time; measured in nanograms times hour per milliliter (ng\*hr/mL). Pharmacokinetic (PK) parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: PK parameter analysis population defined as all subjects randomized and treated who had \> = 1 of the parameters of primary interest in \> = 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity) | 168.1355 ng*hr/mL | Standard Deviation 100.77765 |
| Reference Drug | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity) | 176.1731 ng*hr/mL | Standard Deviation 120.18642 |
Comparison: Natural log transformed AUCinf was analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Adjusted mean difference (Test-Ref) and 90% CI was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean and 90% CI for the ratio. Alternative hypothesis of bioequivalence: (H1: θL \<=µT - µR \<=θU); null hypothesis of inequivalence: (Ho: µT - µR \<θL or µT - µR \>θU).90% CI: [94.57, 103.2]ANOVA
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
AUClast = area under the plasma concentration-time curve from 0 (predose) to the time of the last measureable concentration (Clast). PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 162.5073 ng*hr/mL | Standard Deviation 100.5659 |
| Reference Drug | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 170.4735 ng*hr/mL | Standard Deviation 119.70585 |
Comparison: Natural log transformed AUClast was analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% confidence interval was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean (Test/Reference) and 90% confidence interval for the ratio.90% CI: [94.41, 103.23]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax = maximum observed plasma concentration. Measured in nanograms per milliter (ng/mL); collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Maximum Observed Plasma Concentration (Cmax) | 43.1782 ng/mL | Standard Deviation 31.70609 |
| Reference Drug | Maximum Observed Plasma Concentration (Cmax) | 43.0534 ng/mL | Standard Deviation 36.47166 |
Comparison: Natural log transformed Cmax was analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% confidence intervals were obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean (Test/Reference) and 90% confidence interval for the ratio.90% CI: [95.73, 114.42]ANOVA
Secondary
Plasma Elimination Half-life (t1/2)
t1/2 = terminal elimination half-life in hours; ln 2/kel, where kel is the termination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Plasma Elimination Half-life (t1/2) | 9.330 hours | Standard Deviation 3.1792 |
| Reference Drug | Plasma Elimination Half-life (t1/2) | 9.444 hours | Standard Deviation 4.0157 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence; PK parameters derived from subject's concentration data; collected Period 1, Day 1 to Day 4; Period 2, Day 1 to Day 4.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: PK parameter analysis population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Test Drug | Time to Reach Maximum Plasma Concentration (Tmax) | 1.0 hours |
| Reference Drug | Time to Reach Maximum Plasma Concentration (Tmax) | 1.0 hours |