Bioequivalence Study Comparing A New 10 Mg Atorvastatin Tablet To A 10 Mg Atorvastatin Commercial Tablet

• ClinicalTrials.gov Identifier: NCT00917579
• Recruitment Status: Completed
• First Posted: June 10, 2009
• Results First Posted: October 14, 2009
• Last Update Posted: March 12, 2021
• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Information provided by (Responsible Party): Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Hypercholesterolemia
• Intervention: Drug: Atorvastatin
• Enrollment: 76

Participant Flow

Recruitment Details	Healthy volunteers were recruited from one research center between July 2008 and September 2008.
Pre-assignment Details

Arm/Group Title	Test Drug First, Then Reference Drug	Reference Drug First, Then Test Drug
Arm/Group Description	New (test) 10 milligram (mg) atorvastatin tablet as a single oral dose in the first intervention period, and marketed (reference) 10 mg atorvastatin tablet as a single oral dose in the second intervention period (after washout period).	Marketed (reference) 10 mg atorvastatin commercial tablet (Lipitor®) as a single oral dose in the first intervention period, and new (test) 10 mg atorvastatin tablet as a single oral dose in the second intervention period (after washout period).
Period Title: Period 1: 1st Intervention
Started	39	37
Completed	39	37
Not Completed	0	0
Period Title: Washout >= 2 Weeks
Started	39	37
Completed	37	37
Not Completed	2	0
Reason Not Completed
Adverse Event	1	0
Withdrawal by Subject	1	0
Period Title: Period 2: 2nd Intervention
Started	37	37
Completed	37	37
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Total Number of Participants
Arm/Group Description		All participants received atorvastatin 10 mg tablets (new and marketed).
Overall Number of Baseline Participants		76
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	76 participants
18-44 years		59
45-64 years		17
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	76 participants
	Female	38 50.0%
	Male	38 50.0%

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).
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

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/Group Title	Test Drug	Reference Drug
Arm/Group Description:	New (test) 10 mg atorvastatin tablet as a single oral dose in either first intervention period or second intervention period.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single oral dose in either first intervention period or second intervention period.
Overall Number of Participants Analyzed	76	73
Mean (Standard Deviation); Unit of Measure: ng•hr/mL
	18.3206 (8.26454)	19.2583 (8.79739)

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 within (80%, 125%).
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	Values were back-transformed from the log scale.
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	95.34
	Confidence Interval	90%; 91.33 to 99.52
	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. 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); 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

Outcome Measure Data

Analysis Population Description

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/Group Title	Test Drug	Reference Drug
Arm/Group Description:	New (test) 10 mg atorvastatin tablet as a single oral dose in either first intervention period or second intervention period.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single oral dose in either first intervention period or second intervention period.
Overall Number of Participants Analyzed	76	73
Mean (Standard Deviation); Unit of Measure: ng•hr/mL
	15.7382 (7.88920)	16.5452 (8.71551)

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 the AUCinf and Cmax fell within (80%, 125%). AUCinf method of determination includes AUC last calculated value.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	Values have been back-transformed from the log scale.
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	95.79
	Confidence Interval	90%; 91.07 to 100.76
	Estimation Comments	Parameter estimate = ratio (%) (test/reference) of adjusted geometric means. Log-linear trapezoidal method.

3. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Test Drug	Reference Drug
Arm/Group Description:	New (test) 10 mg atorvastatin tablet as a single oral dose in either first intervention period or second intervention period.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single oral dose in either first intervention period or second intervention period.
Overall Number of Participants Analyzed	76	73
Mean (Standard Deviation); Unit of Measure: ng/mL
	2.6594 (1.44617)	2.8086 (1.23048)

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 within (80%, 125%).
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	Values have been back-transformed from the log scale.
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	91.41
	Confidence Interval	90%; 83.39 to 100.20
	Estimation Comments	Parameter estimate = ratio (%) (test/reference) of adjusted geometric means.

4. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Test Drug	Reference Drug
Arm/Group Description:	New (test) 10 mg atorvastatin tablet as a single oral dose in either first intervention period or second intervention period.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single oral dose in either first intervention period or second intervention period.
Overall Number of Participants Analyzed	76	73
Median (Inter-Quartile Range); Unit of Measure: hours
	1.000; (0.250 to 9.000)	0.5000; (0.250 to 4.000)

5. Secondary Outcome

Title	Plasma Elimination Half-life (t1/2)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Test Drug	Reference Drug
Arm/Group Description:	New (test) 10 mg atorvastatin tablet as a single oral dose in either first intervention period or second intervention period.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single oral dose in either first intervention period or second intervention period.
Overall Number of Participants Analyzed	76	73
Mean (Standard Deviation); Unit of Measure: hours
	10.39 (4.0018)	10.78 (3.9640)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Test Drug	Reference Drug
Arm/Group Description	New (test) 10 mg atorvastatin tablet as a single oral dose.	Marketed (reference) 10 mg atorvastatin tablet (Lipitor®) as a single dose.
All-Cause Mortality
	Test Drug	Reference Drug
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Test Drug	Reference Drug
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1	0
Renal and urinary disorders
Renal colic † 1	1/76 (1.32%)	0/74 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 11.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Test Drug	Reference Drug
	Affected / at Risk (%)	Affected / at Risk (%)
Total	4	15
Gastrointestinal disorders
Constipation † 1	1/76 (1.32%)	4/74 (5.41%)
Dyspepsia † 1	0/76 (0.00%)	1/74 (1.35%)
Nausea † 1	0/76 (0.00%)	2/74 (2.70%)
Vomiting † 1	0/76 (0.00%)	1/74 (1.35%)
Nervous system disorders
Dizziness † 1	1/76 (1.32%)	1/74 (1.35%)
Headache † 1	1/76 (1.32%)	6/74 (8.11%)
Syncope † 1	0/76 (0.00%)	1/74 (1.35%)
Syncope vasovagal † 1	0/76 (0.00%)	2/74 (2.70%)
Psychiatric disorders
Anxiety † 1	0/76 (0.00%)	1/74 (1.35%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion † 1	0/76 (0.00%)	1/74 (1.35%)
Pharyngolaryngeal pain † 1	0/76 (0.00%)	2/74 (2.70%)
Skin and subcutaneous tissue disorders
Rash † 1	1/76 (1.32%)	1/74 (1.35%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 11.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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 ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )
• ClinicalTrials.gov Identifier: NCT00917579
• Other Study ID Numbers: A2581166
• First Submitted: June 8, 2009
• First Posted: June 10, 2009
• Results First Submitted: September 10, 2009
• Results First Posted: October 14, 2009
• Last Update Posted: March 12, 2021