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:

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 (Adult)
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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


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:	May 20, 2014
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 Hyperlipidemias 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 Lipid Regulating Agents

ClinicalTrials.gov processed this record on September 28, 2016