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

Phase 4

Completed

Conditions: Hyperlipidemia
HIV Infections

Interventions: Drug: Pravastatin
Drug: Darunavir
Drug: Ritonavir
Other: Washout

Registration Number: NCT00630734

Lead Sponsor: University of Colorado, Denver

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SLCO1B1 Group 2	Pravastatin	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.
SLCO1B1 Group 1	Washout	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.
SLCO1B1 Group 2	Washout	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.
SLCO1B1 Group 3	Washout	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.
SLCO1B1 Group 1	Pravastatin	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.
SLCO1B1 Group 1	Ritonavir	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.
SLCO1B1 Group 1	Darunavir	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.
SLCO1B1 Group 2	Darunavir	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.
SLCO1B1 Group 2	Ritonavir	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.
SLCO1B1 Group 3	Pravastatin	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.
SLCO1B1 Group 3	Darunavir	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.
SLCO1B1 Group 3	Ritonavir	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.

Primary Outcome Measures

Name	Time	Method
Relative Change in 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	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)	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

Name	Time	Method
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	Dosing interval of 24 hours
Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax)	0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose
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	Dosing interval of 24 hours
Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax)	0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose