Pharmacokinetic Study of Pitavastatin and Ritonavir-Boosted Darunavir or Efavirenz

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01695954
• Collaborator: New York City Health and Hospitals Corporation (Other), Kowa Pharmaceuticals America, Inc. (Industry), University at Buffalo (Other)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 4.2

Study Details

Study Description

Brief Summary

The main goal of this study is to determine how taking efavirenz affects the levels of pitavastatin in the bloodstream when both drugs are taken together and to see how darunavir with ritonavir affects the levels of pitavastatin in the bloodstream. Secondary goals are to see how taking pitavastatin affects the levels in the blood of efavirenz when both drugs are taken together and to see how taking pitavastatin affects the levels in the blood of darunavir.

Condition or Disease	Intervention/Treatment	Phase
Hyperlipidemia; HIV	Drug: Pitavastatin; Drug: Darunavir; Drug: Ritonavir; Drug: Efavirenz	Phase 1

Detailed Description

HIV infected persons are at risk for coronary heart disease due to chronic inflammation associated with the virus itself, the side effects of the antiretroviral (ARV) therapies which can cause elevated cholesterol, and the risk factors such as smoking, high blood pressure and family history of heart disease.

The most commonly prescribed ARVs for treatment of HIV are efavirenz and drugs in the protease inhibitor (PI) class such as darunavir with ritonavir. To treat elevated cholesterol in patients infected with HIV, guidelines recommend the use of statins (a class of lipid lowering drugs). PIs and efavirenz can increase the levels of some statins and reduce the levels of others in the bloodstream. Pitavastatin (Livalo) is a statin approved by the Food and Drug Administration (FDA) for the treatment of high cholesterol.

In order to be able to use pitavastatin safely in HIV-infected patients taking either darunavir with ritonavir or efavirenz, it is important to study how taking pitavastatin with darunavir and ritonavir or pitavastatin with efavirenz affect the levels of each of these drugs in the bloodstream.

Twenty-eight participants will be enrolled in one of two study arms: 14 in Arm A and 14 in Arm B.

Arm A:

Participants will start taking pitavastatin 2 mg tablets every night at bedtime. On day 4 participants will come in for a 14-hour pharmacokinetic (PK) overnight visit and will have about 9 tablespoons of blood drawn. Participants will return 12 hours after the last blood draw for a final blood draw. They will then stop taking pitavastatin. Participants will then start taking one efavirenz 600 mg tablet at bedtime.

On day 14, participants will come in for a second 14-hour visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. Participants will then start taking both pitavastatin and efavirenz at bedtime.

On day 18, participants will come in for a third 14-hour PK visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. They will then stop taking all study drugs and will either come in or receive a final phone call on day 25.

Arm B:

Participants will start taking one pitavastatin 2 mg tablet every morning. On day 4 participants will come in for a 14-hour pharmacokinetic (PK) daytime visit and will have about 9 tablespoons of blood drawn. Participants will return 12 hours after the last blood draw for a final blood draw. They will then stop taking pitavastatin. Participants will then start taking darunavir 400 mg tablets (2) and ritonavir 100 mg tablets (1) every morning.

On day 14, participants will come in for a second 14-hour visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. Participants will then start taking one pitavastatin 2mg tablet, two darunavir 400 mg tablets and one ritonavir 100 mg tablet.

On day 18, participants will come in for a third 14-hour PK visit and will have about 9 tablespoons of blood drawn. They will return 12 hour after the last blood draw for a final blood draw. They will then stop taking all study drugs and will either come in or receive a final phone call on day 25.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The Effect of Efavirenz and Ritonavir-boosted Darunavir on the Pharmacokinetics of the HMG CoA Reductase Inhibitor Pitavastatin
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime.	Drug: Pitavastatin; Pitavastatin 2 mg tablets taken at bedtime in Arm A and in the morning in Arm B.; Other Names: Livalo ; Drug: Efavirenz; Efavirenz 600 mg tablets taken at bedtime in Arm A; Other Names: Sustiva
Experimental: Arm B Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily.	Drug: Pitavastatin; Pitavastatin 2 mg tablets taken at bedtime in Arm A and in the morning in Arm B.; Other Names: Livalo ; Drug: Darunavir; Darunavir 400 mg tablets x 2 taken daily in Arm B; Other Names: Prezista ; Drug: Ritonavir; Ritonavir 100 mg tablets taken daily in Arm B; Other Names: Norvir

Outcome Measures

Primary Outcome Measures

1. AUC [0 to 24 hours]

   24-hour area under the curve (AUC) for pitavastatin when coadministered with efavirenz and with darunavir/ritonavir and 24-hour AUC for efavirenz or darunavir when coadministered with pitavastatin

2. GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin [0 to 24 hours]

   Geometric Mean Ratio (GMR) of 24- Hour Area under the plasma drug concentration-time curve (AUC) of pitavastatin when coadministered with efavirenz or with darunavir/ritonavir over 24 Hour (AUC) of pitavastatin

Secondary Outcome Measures

1. GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir [Day 18]

   Geometric Mean Ratio (GMR) of Cmax for pitavastatin with Efavirenz vs. alone and GMR of Cmax for pitavastatin with darunavir/ritonavir vs. alone was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Absence of HIV-1 infection as documented by any licensed ELISA test kit within 21 days prior to study entry.

• Male or female aged 18-60 years.

• Able and willing to provide informed consent.

• All men and women of reproductive potential must practice adequate birth control to prevent pregnancy from start of the study until completion of the study.

• Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to study entry and day of entry.

• Hemoglobin > 12.5 g/dL for men; > 11.5 g/dL for women;

• Absolute neutrophil count >1,500 cells/mm3;

• Platelet count > 100,000 platelets/mm3;

• AST (SGOT)/ALT (SGPT) <1.5X ULN;

• Creatinine <1.5 X ULN

• Subject is within 20% (+/-) of ideal body weight and must weigh at least 50 kg

Exclusion Criteria:

• Use of illicit drugs or alcohol which would interfere with the completion of this study.

• Pregnancy or breast-feeding.

• History of chronic illnesses such as hypertension, coronary artery disease, arthritis, diabetes, or any chronic gastrointestinal conditions which might interfere with drug absorption.

• Any medical condition which, in the opinion of the investigator, would interfere with the subjects ability to participate in this protocol.

• Use of prohibited protocol-specified drugs, prescription or over-the-counter within 14 days prior to study entry.

• Participation in any investigational drug studies within 30 days prior to study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bellevue/NYU AIDS Clinical Trials Unit	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health
• New York City Health and Hospitals Corporation
• Kowa Pharmaceuticals America, Inc.
• University at Buffalo

Investigators

• Principal Investigator: Judith Aberg, M.D., NYU School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT01695954
• Other Study ID Numbers: 11-01787
• First Posted: Sep 28, 2012
• Last Update Posted: Aug 11, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by NYU Langone Health: HIV; Hyperlipidemia; Pharmacokinetics; Statins; Darunavir; Efavirenz; Pitavastatin
• Additional relevant MeSH terms: Hyperlipidemias; Hyperlipoproteinemias; Ritonavir; Darunavir; Efavirenz; Pitavastatin

Study Results

Participant Flow

Recruitment Details	Accrual began August 24, 2012 and ended January, 8, 2013. All study procedures took place at the NYU/Bellevue Clinical Trials Unit and NYU Clinical and Translational Science Institute.

Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)	Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime.	Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily.
Period Title: Overall Study
STARTED	18	16
COMPLETED	14	14
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)	Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)	Total
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime.	Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily.	Total of all reporting groups
Overall Participants	18	16	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	16 100%	34 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	8 44.4%	7 43.8%	15 44.1%
Male	10 55.6%	9 56.3%	19 55.9%

Outcome Measures

1. Primary Outcome

Title	AUC
Description	24-hour area under the curve (AUC) for pitavastatin when coadministered with efavirenz and with darunavir/ritonavir and 24-hour AUC for efavirenz or darunavir when coadministered with pitavastatin
Time Frame	0 to 24 hours

Outcome Measure Data

Analysis Population Description

Subjects who completed all visits

Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)	Arm B: (Pitavastatin and Darunavir)
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime for the first 4 days, then efavirenz 600 mg at bedtime for the next 10 days and both pitavastatin 2 mg and efavirenz 600 mg at bedtime for the final 4 days. Blood will be drawn on days 0, 4, 14 and 18.	Subjects in arm will receive pitavastatin 2 mg daily for the first 4 days, then darunavir 400 mg x 2 tabs and ritonavir 100 mg x 1 tab daily for the next 10 days and will receive both pitavastatin 2 mg and darunavir 400 mg x 2 tabs and ritonavir 100 mg x 1 tab daily for the final 4 days. Blood will be drawn on days 0, 4, 14, and 18.
Measure Participants	18	16
Mean (Standard Deviation) [ng*hr/mL]	85.3 (5.72)	62.8 (6.24)

2. Secondary Outcome

Title	GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir
Description	Geometric Mean Ratio (GMR) of Cmax for pitavastatin with Efavirenz vs. alone and GMR of Cmax for pitavastatin with darunavir/ritonavir vs. alone was reported.
Time Frame	Day 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)	Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime.	Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily.
Measure Participants	18	16
Geometric Mean (90% Confidence Interval) [ng/mL]	1.20	0.93

3. Primary Outcome

Title	GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin
Description	Geometric Mean Ratio (GMR) of 24- Hour Area under the plasma drug concentration-time curve (AUC) of pitavastatin when coadministered with efavirenz or with darunavir/ritonavir over 24 Hour (AUC) of pitavastatin
Time Frame	0 to 24 hours

Outcome Measure Data

Analysis Population Description

Subjects who completed all visits

Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)	Arm B: (Pitavastatin and Darunavir)
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime for the first 4 days, then efavirenz 600 mg at bedtime for the next 10 days and both pitavastatin 2 mg and efavirenz 600 mg at bedtime for the final 4 days. Blood will be drawn on days 0, 4, 14 and 18.	Subjects in arm will receive pitavastatin 2 mg daily for the first 4 days, then darunavir 400 mg x 2 tabs and ritonavir 100 mg x 1 tab daily for the next 10 days and will receive both pitavastatin 2 mg and darunavir 400 mg x 2 tabs and ritonavir 100 mg x 1 tab daily for the final 4 days. Blood will be drawn on days 0, 4, 14, and 18.
Measure Participants	18	16
GMR of Pitavastatin with (EFV or DRV)/Pitavastatin	.89	.91
GMR of (EFV or DRV) with Pitavastatin/(EFV or DRV)	.90	1.08

Adverse Events

Time Frame	7 months.
Arm/Group Title	Arm A: (Pitavastatin and Efavirenz)		Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
Arm/Group Description	Subjects assigned to Arm A will receive pitavastatin 2 mg at bedtime and efavirenz 600 mg at bedtime.		Subjects assigned to Arm B will receive pitavastatin 2 mg daily and darunavir 800 mg with ritonavir 100 mg daily.
All Cause Mortality
	Arm A: (Pitavastatin and Efavirenz)		Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: (Pitavastatin and Efavirenz)		Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: (Pitavastatin and Efavirenz)		Arm B: (Pitavastatin and Ritonavir-boosted Darunavir)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/18 (77.8%)		7/16 (43.8%)
Blood and lymphatic system disorders
Anemia	1/18 (5.6%)	1	0/16 (0%)	0
Leukocytosis	1/18 (5.6%)	1	0/16 (0%)	0
Gastrointestinal disorders
Vomiting	1/18 (5.6%)	1	0/16 (0%)	0
Diarrhea	1/18 (5.6%)	1	1/16 (6.3%)	1
General disorders
Fever	1/18 (5.6%)	1	0/16 (0%)	0
CPK elevation	0/18 (0%)	0	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Pain at venipuncture site	0/18 (0%)	0	1/16 (6.3%)	1
Nervous system disorders
Headache	2/18 (11.1%)	4	1/16 (6.3%)	1
Dizziness	2/18 (11.1%)	3	0/16 (0%)	0
Nausea	2/18 (11.1%)	2	0/16 (0%)	0
Vivid dreams	1/18 (5.6%)	2	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders
Rhinorrhea	1/18 (5.6%)	2	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Rash	1/18 (5.6%)	1	2/16 (12.5%)	2

Limitations/Caveats

Pitavastatin levels for 4 subjects enrolled in Arm B were lost due to emergency transfer of specimens to temporary storage facility during Hurricane Sandy.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.