Genetic Predictors of Variability in the Drug-drug Interaction Between Darunavir/Ritonavir and Pravastatin

Study Overview
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Brief Summary
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Pravastatin (Pravachol) is approved by the Food and Drug Administration (FDA) and is used to treat high cholesterol. Darunavir (Prezista) and ritonavir (Norvir) are approved by the Food and Drug Administration (FDA) to treat HIV infection. When darunavir and ritonavir are given with pravastatin, they can increase the blood levels of pravastatin. The degree of this interaction varies from person to person. The way that darunavir and ritonavir interact with pravastatin may be affected by a person's genetic make-up. Genetic factors (or DNA) are those that people are born with and that make each person unique. Genetic differences are the reason why one person's body traits such as height and hair color are different from another person's body traits. Genetic differences can also affect the way a medication works in the body or the way two medications interact in the body. The purpose of this clinical study is to determine if a person's genetic make-up affects the way darunavir and ritonavir interact with pravastatin in the body.

Official Title
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Genetic Predictors of Pharmacokinetic Variability in the Drug-drug Interaction Between Darunavir/Ritonavir and Pravastatin: the Role of SLCO1B1 Polymorphisms.

Conditions
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HIV Infections, Hyperlipidemia

Intervention / Treatment
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* Drug: Pravastatin
* Drug: Darunavir
* Drug: Ritonavir
* Drug: Pravastatin
* Other: Washout


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, HIV-negative volunteers Exclusion Criteria: Currently active or chronic cardiovascular, hepatic, renal, pancreatic, gastrointestinal, neurologic, hematologic, psychiatric, metabolic, respiratory, inflammatory, or infectious disease Chronic pancreatitis History of rhabdomyolysis History of statin-associated myopathy Active malignancy History of significant skin disease, food allergy, drug allergy, dermatitis, eczema, psoriasis Pregnancy/breastfeeding HIV positive and/or AIDS serum creatinine grade 1 or greater (≥ 1.1 x upper limit of laboratory normal range [ULN]); hemoglobin grade 1 or greater (≤ 10.9 g/dL); platelet count grade 1 or greater (≤ 124.999 x 109/L); absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (≥ 1.25 x ULN); total bilirubin grade 1 or greater (≥ 1.1 x ULN) serum lipase grade 1 or greater (≥ 1.1 x ULN) serum amylase grade 1 or greater (≥ 1.1 x ULN) any other laboratory abnormality of grade 2 or above

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SLCO1B1 Group 1<br>Participants with the SLCO1B1 *1A/*1A diplotype; Interventions: pravastatin 40 mg by mouth once daily on days 1-4, washout on days 5-11, darunavir 600 mg and ritonavir 100 mg by mouth twice daily on days 12-18, pravastatin 40 mg by mouth once daily on days 15-18. | Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 1-4<br>* Other names: Pravachol;Drug: Darunavir<br>* Darunavir 600mg by mouth twice daily on days 12-18<br>* Other names: Prezista;Drug: Ritonavir<br>* Ritonavir 100mg by mouth twice daily on days 12-18<br>* Other names: Norvir;Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 15-18<br>* Other names: Pravachol;Other: Washout<br>* Washout (no medication) on days 5-11.<br>|
| Experimental: SLCO1B1 Group 2<br>Participants with the SLCO1B1 *1A/*1B or *1B/*1B diplotype; Interventions: Pravastatin 40 mg by mouth once daily on days 1-4, washout on days 5-11, darunavir 600 mg and ritonavir 100 mg by mouth twice daily on days 12-18, pravastatin 40 mg by mouth once daily on days 15-18. | Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 1-4<br>* Other names: Pravachol;Drug: Darunavir<br>* Darunavir 600mg by mouth twice daily on days 12-18<br>* Other names: Prezista;Drug: Ritonavir<br>* Ritonavir 100mg by mouth twice daily on days 12-18<br>* Other names: Norvir;Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 15-18<br>* Other names: Pravachol;Other: Washout<br>* Washout (no medication) on days 5-11.<br>|
| Experimental: SLCO1B1 Group 3<br>Participants who carry at least one SLCO1B1 *5, *15, or *17 diplotype; Interventions: Pravastatin 40 mg by mouth once daily on days 1-4, washout on days 5-11, darunavir 600 mg and ritonavir 100 mg by mouth twice daily on days 12-18, pravastatin 40 mg by mouth once daily on days 15-18. | Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 1-4<br>* Other names: Pravachol;Drug: Darunavir<br>* Darunavir 600mg by mouth twice daily on days 12-18<br>* Other names: Prezista;Drug: Ritonavir<br>* Ritonavir 100mg by mouth twice daily on days 12-18<br>* Other names: Norvir;Drug: Pravastatin<br>* Pravastatin 40 mg by mouth daily on days 15-18<br>* Other names: Pravachol;Other: Washout<br>* Washout (no medication) on days 5-11.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | AUC of pravastatin when administered with darunavir/ritonavir divided by AUC of pravastatin when administered alone. The AUC was measured over a 24-hour dosing interval. | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 
| Relative Change in Pravastatin Maximum Plasma Concentration (Cmax) | Cmax of pravastatin when administered with darunavir/ritonavir divided by the Cmax of pravastatin when administered alone. | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | Dosing interval of 24 hours | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 
| Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 
| Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | Dosing interval of 24 hours | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 
| Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Pravastatin, Darunavir, Ritonavir, Genetic