Bioequivalence Study Comparing A New 80 Mg Atorvastatin Tablet To A 80 Mg Atorvastatin Commercial Tablet

Sponsor
Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00917644
Collaborator
(none)
76
1
2
2
37.3

Study Details

Study Description

Brief Summary

To determine whether new 80 mg atorvastatin tablets are bioequivalent to 80 mg commercial atorvastatin tablets (Lipitor®).

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
76 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
An Open Label, Randomized, Single Dose, Two-Way Crossover Bioequivalence Study Comparing A New 80 Mg Atorvastatin Tablet To A 80 Mg Atorvastatin Commercial Tablet In Healthy Subjects
Study Start Date :
Jul 1, 2008
Actual Primary Completion Date :
Sep 1, 2008
Actual Study Completion Date :
Sep 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Other: Reference

80 mg atorvastatin tablets

Drug: Atorvastatin
A single 80 mg dose of marketed 80 mg atorvastatin tablets

Experimental: Test

New 80 mg atorvastatin tablets

Genetic: Atorvastatin
A single dose of new formulation of 80 mg atorvastatin tablets

Outcome Measures

Primary Outcome Measures

  1. 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.

  2. 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.

  3. 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 Outcome Measures

  1. 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.

  2. 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 55 Years
Sexes Eligible for Study:
All
Accepts 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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Pfizer Investigational Site Miami Florida United States 33169

Sponsors and Collaborators

  • Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
ClinicalTrials.gov Identifier:
NCT00917644
Other Study ID Numbers:
  • A2581167
First Posted:
Jun 10, 2009
Last Update Posted:
Feb 21, 2021
Last Verified:
Feb 1, 2021
Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Test Drug First Reference Drug First
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period and marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the second intervention period (after washout period). Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period and new (test) 80 mg atorvastatin tablets as a single dose in the second intervention period (after washout period).
Period Title: Period 1: First Intervention
STARTED 39 37
COMPLETED 39 37
NOT COMPLETED 0 0
Period Title: Period 1: First Intervention
STARTED 39 37
COMPLETED 37 37
NOT COMPLETED 2 0
Period Title: Period 1: First Intervention
STARTED 37 37
COMPLETED 36 37
NOT COMPLETED 1 0

Baseline Characteristics

Arm/Group Title Total Study Population
Arm/Group Description New 80 milligram (mg) atorvastatin tablets (test); marketed 80 mg atorvastatin commercial tablet (Lipitor®) (reference)
Overall Participants 76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
41.0
(9.0)
Sex: Female, Male (Count of Participants)
Female
35
46.1%
Male
41
53.9%

Outcome Measures

1. Primary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Infinity)
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
Measure Participants 76 74
Mean (Standard Deviation) [ng*hr/mL]
168.1355
(100.77765)
176.1731
(120.18642)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Test Drug, Reference Drug
Comments 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).
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments Bioequivalence of the two treatments was concluded if the 90% confidence intervals for the ratio of adjusted geometric means for both AUCinf and Cmax fell wholly within (80%, 125%)
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 98.79
Confidence Interval () 90%
94.57 to 103.20
Parameter Dispersion Type:
Value:
Estimation Comments Parameter estimate = ratio (%) (test/reference) of adjusted geometric means. AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
2. Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax)
Description 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

Outcome Measure Data

Analysis Population Description
PK parameter analysis population
Arm/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
Measure Participants 76 74
Median (Full Range) [hours]
1.0
1.0
3. Primary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Description 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

Outcome Measure Data

Analysis Population Description
PK parameter analysis population
Arm/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
Measure Participants 76 74
Mean (Standard Deviation) [ng*hr/mL]
162.5073
(100.56590)
170.4735
(119.70585)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Test Drug, Reference Drug
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments Bioequivalence of the two treatments was concluded if the 90% confidence intervals for the ratio of adjusted geometric means for both AUCinf and Cmax fell wholly within (80%, 125%). AUCinf method of determination includes AUClast calculated value.
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 98.72
Confidence Interval () 90%
94.41 to 103.23
Parameter Dispersion Type:
Value:
Estimation Comments Parameter estimate = ratio (%) (test/reference) of adjusted geometric means. Log-linear trapezoidal method.
4. Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax)
Description 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

Outcome Measure Data

Analysis Population Description
PK parameter analysis population
Arm/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
Measure Participants 76 74
Mean (Standard Deviation) [ng/mL]
43.1782
(31.70609)
43.0534
(36.47166)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Test Drug, Reference Drug
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments Bioequivalence of the two treatments was concluded if the 90% confidence intervals for the ratio of adjusted geometric means for both AUCinf and Cmax fell wholly within (80%, 125%)
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Ratio of adjusted geometric means
Estimated Value 104.66
Confidence Interval () 90%
95.73 to 114.42
Parameter Dispersion Type:
Value:
Estimation Comments Parameter estimate = ratio (%) (test/reference) of adjusted geometric means. Observed directly from data.
5. Secondary Outcome
Title Plasma Elimination Half-life (t1/2)
Description 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

Outcome Measure Data

Analysis Population Description
PK parameter analysis population
Arm/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
Measure Participants 76 74
Mean (Standard Deviation) [hours]
9.330
(3.1792)
9.444
(4.0157)

Adverse Events

Time Frame
Adverse Event Reporting Description
Arm/Group Title Test Drug Reference Drug
Arm/Group Description New (test) 80 milligram (mg) atorvastatin tablets as a single dose in the first intervention period or second intervention period. Marketed (reference) 80 mg atorvastatin commercial tablet (Lipitor®) as a single dose in the first intervention period or second intervention period.
All Cause Mortality
Test Drug Reference Drug
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
Test Drug Reference Drug
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/76 (0%) 0/74 (0%)
Other (Not Including Serious) Adverse Events
Test Drug Reference Drug
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 11/76 (14.5%) 4/74 (5.4%)
Gastrointestinal disorders
Abdominal pain 1/76 (1.3%) 0/74 (0%)
Nausea 1/76 (1.3%) 0/74 (0%)
Toothache 1/76 (1.3%) 0/74 (0%)
Vomiting 1/76 (1.3%) 0/74 (0%)
General disorders
Fatigue 0/76 (0%) 1/74 (1.4%)
Infections and infestations
Dermatophytosis 1/76 (1.3%) 0/74 (0%)
Nasopharyngitis 1/76 (1.3%) 0/74 (0%)
Nervous system disorders
Headache 6/76 (7.9%) 3/74 (4.1%)
Paraesthesia 1/76 (1.3%) 0/74 (0%)
Skin and subcutaneous tissue disorders
Rash 1/76 (1.3%) 0/74 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer, Inc.
Phone 1-800-718-1021
Email ClinicalTrials.govCallCenter@pfizer.com
Responsible Party:
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
ClinicalTrials.gov Identifier:
NCT00917644
Other Study ID Numbers:
  • A2581167
First Posted:
Jun 10, 2009
Last Update Posted:
Feb 21, 2021
Last Verified:
Feb 1, 2021