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

NCT00630734 | Completed Phase 4 Results DMC

• 2 other identifiers: 07-0272TMC114HIV4003
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV Infections; Hyperlipidemia

Keywords

HIV; Pravastatin; Darunavir; Ritonavir; Genetic

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval

  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

  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

Other Outcomes (4)

• Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval

  0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose

• Darunavir Maximum Plasma Concentration (Cmax)

  0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose

• Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval

  0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose

Study Arms (3)

SLCO1B1 Group 1

EXPERIMENTAL

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; Drug: Darunavir; Drug: Ritonavir; Other: Washout

SLCO1B1 Group 2

EXPERIMENTAL

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; Drug: Darunavir; Drug: Ritonavir; Other: Washout

SLCO1B1 Group 3

EXPERIMENTAL

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; Drug: Darunavir; Drug: Ritonavir; Other: Washout

Interventions

Pravastatin DRUG

Pravastatin 40 mg by mouth daily on days 1-4

Also known as: Pravachol

SLCO1B1 Group 1; SLCO1B1 Group 2; SLCO1B1 Group 3

Darunavir DRUG

Darunavir 600mg by mouth twice daily on days 12-18

Also known as: Prezista

SLCO1B1 Group 1; SLCO1B1 Group 2; SLCO1B1 Group 3

Ritonavir DRUG

Ritonavir 100mg by mouth twice daily on days 12-18

Also known as: Norvir

SLCO1B1 Group 1; SLCO1B1 Group 2; SLCO1B1 Group 3

Washout OTHER

Washout (no medication) on days 5-11.

SLCO1B1 Group 1; SLCO1B1 Group 2; SLCO1B1 Group 3

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy, HIV-negative volunteers

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA: collaborator

Study Sites (1)

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

HIV Infections; Hyperlipidemias

Interventions

Pravastatin; Darunavir; Ritonavir; WASH protein, Drosophila

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Sulfonamides; Amides; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles

Limitations and Caveats

The study included only heterozygous carriers of the SLCO1B1 \*15 and \*17 haplotypes. Pravastatin urine concentrations were not measured; therefore the impact of darunavir/ritonavir on pravastatin renal clearance was not assessed in this population.

Results Point of Contact

• Title: Christina Aquilante, Pharm.D.
• Organization: University of Colorado Denver

christina.aquilante@ucdenver.edu

303-724-6126

Study Officials

• Christina L Aquilante, PharmD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2008
• First Posted: March 7, 2008
• Study Start: February 1, 2008
• Primary Completion: October 1, 2009
• Study Completion: September 1, 2010
• Last Updated: May 22, 2014
• Results First Posted: November 15, 2012

Record last verified: 2014-05

Locations

US (1)