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

Purpose

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	Intervention	Phase
HIV Infections Hyperlipidemia	Drug: Pravastatin Drug: Darunavir Drug: Ritonavir Other: Washout	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Parallel Assignment Masking: 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.

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency

MedlinePlus related topics: Drug Reactions HIV/AIDS

Drug Information available for: Pravastatin Pravastatin sodium Ritonavir Darunavir Darunavir ethanolate

U.S. FDA Resources

Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]
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.
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 ] [ Designated as safety issue: No ]
Cmax of pravastatin when administered with darunavir/ritonavir divided by the Cmax of pravastatin when administered alone.

Secondary Outcome Measures:

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 ] [ Designated as safety issue: No ]
Dosing interval of 24 hours
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Dosing interval of 24 hours
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 ] [ Designated as safety issue: No ]

Other Outcome Measures:

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 ] [ Designated as safety issue: No ]
AUC of darunavir over a 12-hour dosing interval.
Darunavir Maximum Plasma Concentration (Cmax) [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
Cmax of darunavir over a 12-hour dosing interval
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 ] [ Designated as safety issue: No ]
AUC of ritonavir over a 12-hour dosing interval.
Ritonavir Maximum Plasma Concentration (Cmax) [ Time Frame: 0,1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
Cmax of ritonavir over a 12-hour dosing interval

Enrollment:	32
Study Start Date:	February 2008
Study Completion Date:	September 2010
Primary Completion Date:	October 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: 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

No publications provided

Responsible Party:	University of Colorado, Denver
ClinicalTrials.gov Identifier:	NCT00630734 History of Changes
Other Study ID Numbers:	07-0272, TMC114HIV4003
Study First Received:	February 28, 2008
Results First Received:	September 12, 2011
Last Updated:	November 19, 2012
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board

Keywords provided by University of Colorado, Denver:

HIV
Pravastatin
Darunavir
Ritonavir
Genetic

Additional relevant MeSH terms:

HIV Infections
Acquired Immunodeficiency Syndrome
Hyperlipidemias
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases

Pravastatin
Ritonavir
Darunavir
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
HIV Protease Inhibitors
Protease Inhibitors
Anti-HIV Agents

ClinicalTrials.gov processed this record on March 03, 2013