Hypercholesterolemia
Conditions
Keywords
Bioequivalence, pharmacokinetics, atorvastatin
Brief summary
• To determine whether new 10 mg atorvastatin tablets are bioequivalent to 10 mg commercial atorvastatin tablets (Lipitor®).
Interventions
DRUGAtorvastatin
A single 10 mg dose of marketed 10 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). |
| 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); measured in nanograms times hour per milliliter (ng•hr/mL). |
| 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). |
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). |
| 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. |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers were recruited from one research center between July 2008 and September 2008.
Participants by arm
| Arm | Count |
|---|---|
| Total Number of Participants All participants received atorvastatin 10 mg tablets (new and marketed). | 76 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout >= 2 Weeks | Adverse Event | 1 | 0 |
| Washout >= 2 Weeks | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total Number of Participants |
|---|---|
| Age, Customized 18-44 years | 59 participants |
| Age, Customized 45-64 years | 17 participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / — | 15 / — |
| serious Total, serious adverse events | 1 / — | 0 / — |
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).
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 10, 12, 24, 36, 48, 72 hours post dose
Population: Pharmacokinetic (PK) parameter analysis population: all subjects enrolled and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Only 73 subjects contributed to the PK analysis in the reference group as plasma concentrations for 1 subject were below the limit of quantification, except 1 time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity) | 18.3206 ng•hr/mL | Standard Deviation 8.26454 |
| Reference Drug | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity) | 19.2583 ng•hr/mL | Standard Deviation 8.79739 |
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: [91.33, 99.52]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); measured in nanograms times hour per milliliter (ng•hr/mL).
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: all subjects enrolled and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Only 73 subjects contributed to the PK analysis in the reference group as plasma concentrations for 1 subject were below the limit of quantification, with the exception of 1 time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 15.7382 ng•hr/mL | Standard Deviation 7.8892 |
| Reference Drug | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 16.5452 ng•hr/mL | Standard Deviation 8.71551 |
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: [91.07, 100.76]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax = maximum observed plasma concentration. Measured in nanograms per milliter (ng/mL).
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: all subjects enrolled and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Only 73 subjects contributed to the PK analysis in the reference group as plasma concentrations for 1 subject were below the limit of quantification, with the exception of 1 time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Maximum Observed Plasma Concentration (Cmax) | 2.6594 ng/mL | Standard Deviation 1.44617 |
| Reference Drug | Maximum Observed Plasma Concentration (Cmax) | 2.8086 ng/mL | Standard Deviation 1.23048 |
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: [83.39, 100.2]ANOVA
Secondary
Plasma Elimination Half-life (t1/2)
t1/2 = terminal elimination half-life in hours.
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: all subjects enrolled and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Only 73 subjects contributed to the PK analysis in the reference group as plasma concentrations for 1 subject were below the limit of quantification, with the exception of 1 time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Drug | Plasma Elimination Half-life (t1/2) | 10.39 hours | Standard Deviation 4.0018 |
| Reference Drug | Plasma Elimination Half-life (t1/2) | 10.78 hours | Standard Deviation 3.964 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Tmax = time (hours) to maximum plasma concentration (Cmax).
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: all subjects enrolled and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Only 73 subjects contributed to the PK analysis in the reference group as plasma concentrations for 1 subject were below the limit of quantification, with the exception of 1 time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Test Drug | Time to Reach Maximum Plasma Concentration (Tmax) | 1.000 hours |
| Reference Drug | Time to Reach Maximum Plasma Concentration (Tmax) | 0.5000 hours |