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

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00917579
• Collaborator: (none)
• Enrollment: 76
• Location: 1
• Arms: 2
• Duration (Months): 2
• Patients Per Site Per Month: 37.3

Study Details

Study Description

Brief Summary

• To determine whether new 10 mg atorvastatin tablets are bioequivalent to 10 mg commercial atorvastatin tablets (Lipitor®).

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: Atorvastatin; Drug: Atorvastatin	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 10 Mg Atorvastatin Tablet To A 10 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 10 mg atorvastatin	Drug: Atorvastatin; A single 10 mg dose of marketed 10 mg atorvastatin tablets
Experimental: Test New 10 mg atorvastatin tablet	Drug: Atorvastatin; A single 10 mg dose of new formulation of 10 mg atorvastatin

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).

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); measured in nanograms times hour per milliliter (ng•hr/mL).

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).

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).

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.

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:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT00917579
• Other Study ID Numbers: A2581166
• First Posted: Jun 10, 2009
• Last Update Posted: Mar 12, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: Bioequivalence, pharmacokinetics, atorvastatin
• Additional relevant MeSH terms: Hypercholesterolemia; Atorvastatin

Study Results

Participant Flow

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

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: Period 1: 1st Intervention
STARTED	39	37
COMPLETED	37	37
NOT COMPLETED	2	0
Period Title: Period 1: 1st 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 Participants	76
Age, Customized (participants) [Number]
18-44 years	59 77.6%
45-64 years	17 22.4%
Sex: Female, Male (Count of Participants)
Female	38 50%
Male	38 50%

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.
Measure Participants	76	73
Mean (Standard Deviation) [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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	95.34
	Confidence Interval	() 90%; 91.33 to 99.52
	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. 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.
Measure Participants	76	73
Mean (Standard Deviation) [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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	95.79
	Confidence Interval	() 90%; 91.07 to 100.76
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	76	73
Mean (Standard Deviation) [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
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of adjusted geometric means
	Estimated Value	91.41
	Confidence Interval	() 90%; 83.39 to 100.20
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	76	73
Median (Inter-Quartile Range) [hours]	1.000	0.5000

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.
Measure Participants	76	73
Mean (Standard Deviation) [hours]	10.39 (4.0018)	10.78 (3.9640)

Adverse Events

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Test Drug		Reference Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/ (NaN)		0/ (NaN)
Renal and urinary disorders
Renal colic	1/76 (1.3%)		0/74 (0%)
Other (Not Including Serious) Adverse Events
	Test Drug		Reference Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/ (NaN)		15/ (NaN)
Gastrointestinal disorders
Constipation	1/76 (1.3%)		4/74 (5.4%)
Dyspepsia	0/76 (0%)		1/74 (1.4%)
Nausea	0/76 (0%)		2/74 (2.7%)
Vomiting	0/76 (0%)		1/74 (1.4%)
Nervous system disorders
Dizziness	1/76 (1.3%)		1/74 (1.4%)
Headache	1/76 (1.3%)		6/74 (8.1%)
Syncope	0/76 (0%)		1/74 (1.4%)
Syncope vasovagal	0/76 (0%)		2/74 (2.7%)
Psychiatric disorders
Anxiety	0/76 (0%)		1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/76 (0%)		1/74 (1.4%)
Pharyngolaryngeal pain	0/76 (0%)		2/74 (2.7%)
Skin and subcutaneous tissue disorders
Rash	1/76 (1.3%)		1/74 (1.4%)

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.