Pharmacokinetic Study of Pitavastatin and Ritonavir-Boosted Darunavir or Efavirenz

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Effect of Efavirenz and Ritonavir-boosted Darunavir on the Pharmacokinetics of the HMG CoA Reductase Inhibitor Pitavastatin

Conditions
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HIV, Hyperlipidemia

Intervention / Treatment
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* Drug: Pitavastatin
* Drug: Darunavir
* Drug: Ritonavir
* Drug: Efavirenz


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | 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 | 0 to 24 hours | 
| GMR of 24- Hour AUC of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir Over 24 Hour AUC of Pitavastatin | 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 | 0 to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GMR of Cmax of Pitavastatin When Coadministered With Efavirenz or With Darunavir/Ritonavir | 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. | Day 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Hyperlipidemia, Pharmacokinetics, Statins, Darunavir, Efavirenz, Pitavastatin