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

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ClinicalTrials.gov Identifier: NCT00630734
Recruitment Status : Completed
First Posted : March 7, 2008
Results First Posted : November 15, 2012
Last Update Posted : May 22, 2014
Sponsor:
Collaborator:
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
Information provided by (Responsible Party):
University of Colorado, Denver

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV Infections Hyperlipidemia Drug: Pravastatin Drug: Darunavir Drug: Ritonavir Other: Washout Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Genetic Predictors of Pharmacokinetic Variability in the Drug-drug Interaction Between Darunavir/Ritonavir and Pravastatin: the Role of SLCO1B1 Polymorphisms.
Study Start Date : February 2008
Actual Primary Completion Date : October 2009
Actual Study Completion Date : September 2010

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U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: SLCO1B1 Group 1
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
Pravastatin 40 mg by mouth daily on days 1-4
Other Name: Pravachol
Drug: Darunavir
Darunavir 600mg by mouth twice daily on days 12-18
Other Name: Prezista
Drug: Ritonavir
Ritonavir 100mg by mouth twice daily on days 12-18
Other Name: Norvir
Drug: Pravastatin
Pravastatin 40 mg by mouth daily on days 15-18
Other Name: Pravachol
Other: Washout
Washout (no medication) on days 5-11.
Experimental: SLCO1B1 Group 2
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
Pravastatin 40 mg by mouth daily on days 1-4
Other Name: Pravachol
Drug: Darunavir
Darunavir 600mg by mouth twice daily on days 12-18
Other Name: Prezista
Drug: Ritonavir
Ritonavir 100mg by mouth twice daily on days 12-18
Other Name: Norvir
Drug: Pravastatin
Pravastatin 40 mg by mouth daily on days 15-18
Other Name: Pravachol
Other: Washout
Washout (no medication) on days 5-11.
Experimental: SLCO1B1 Group 3
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
Pravastatin 40 mg by mouth daily on days 1-4
Other Name: Pravachol
Drug: Darunavir
Darunavir 600mg by mouth twice daily on days 12-18
Other Name: Prezista
Drug: Ritonavir
Ritonavir 100mg by mouth twice daily on days 12-18
Other Name: Norvir
Drug: Pravastatin
Pravastatin 40 mg by mouth daily on days 15-18
Other Name: Pravachol
Other: Washout
Washout (no medication) on days 5-11.


Outcome Measures
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Primary Outcome Measures :
  1. Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]
    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.

  2. Relative Change in Pravastatin Maximum Plasma Concentration (Cmax) [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]
    Cmax of pravastatin when administered with darunavir/ritonavir divided by the Cmax of pravastatin when administered alone.


Secondary Outcome Measures :
  1. Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]
    Dosing interval of 24 hours

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

  4. Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax) [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

Other Outcome Measures:
  1. Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]
    AUC of darunavir over a 12-hour dosing interval.

  2. Darunavir Maximum Plasma Concentration (Cmax) [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]
    Cmax of darunavir over a 12-hour dosing interval

  3. Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]
    AUC of ritonavir over a 12-hour dosing interval.

  4. Ritonavir Maximum Plasma Concentration (Cmax) [ Time Frame: 0,1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]
    Cmax of ritonavir over a 12-hour dosing interval


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00630734


Locations
United States, Colorado
University of Colorado Denver
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
Investigators
Principal Investigator: Christina L Aquilante, PharmD University of Colorado, Denver
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT00630734     History of Changes
Other Study ID Numbers: 07-0272
TMC114HIV4003
First Posted: March 7, 2008    Key Record Dates
Results First Posted: November 15, 2012
Last Update Posted: May 22, 2014
Last Verified: May 2014

Keywords provided by University of Colorado, Denver:
HIV
Pravastatin
Darunavir
Ritonavir
Genetic

Additional relevant MeSH terms:
HIV Infections
Hyperlipidemias
Hyperlipoproteinemias
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Ritonavir
 Darunavir
Pravastatin
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites