HIV Infections, Hyperlipidemia
Conditions
Keywords
HIV, Pravastatin, Darunavir, Ritonavir, Genetic
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.
Interventions
DRUGPravastatin
Pravastatin 40 mg by mouth daily on days 1-4
DRUGDarunavir
Darunavir 600mg by mouth twice daily on days 12-18
DRUGRitonavir
Ritonavir 100mg by mouth twice daily on days 12-18
OTHERWashout
Washout (no medication) on days 5-11.
Sponsors
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Pravastatin Alone: 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 + 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 | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | AUC of ritonavir over a 12-hour dosing interval. |
| Ritonavir Maximum Plasma Concentration (Cmax) | 0,1, 2, 3, 4, 5, 6, 8, 12 hours post-dose | Cmax of ritonavir over a 12-hour dosing interval |
| Darunavir Maximum Plasma Concentration (Cmax) | 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose | Cmax of darunavir over a 12-hour dosing interval |
| 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 | AUC of darunavir over a 12-hour dosing interval. |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers were recruited from the Denver metro area between March 2008 and September 2009.
Pre-assignment details
Participants were genetically screened for solute carrier organic anion transporter family, member 1B1 (SLCO1B1) diplotypes as follows: Group 1, \*1A/\*1A (reference diplotype); Group 2, \*1A/\*1B or \*1B/\*1B diplotypes; and Group 3, subjects with at least one copy of the \*5, \*15, or \*17 haplotype.
Participants by arm
| Arm | Count |
|---|---|
| SLCO1B1 Group 1 SLCO1B1 \*1A/\*1A diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18 | 9 |
| SLCO1B1 Group 2 SLCO1B1 \*1A/\*1B or \*1B/\*1B diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18 | 12 |
| SLCO1B1 Group 3 Carriers of at least one SLCO1B1 \*5, \*15, or \*17 haplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18 | 7 |
| Total | 28 |
Baseline characteristics
| Characteristic | SLCO1B1 Group 2 | SLCO1B1 Group 3 | SLCO1B1 Group 1 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 7 Participants | 9 Participants | 28 Participants |
| Age, Continuous | 37 years STANDARD_DEVIATION 12 | 39 years STANDARD_DEVIATION 11 | 36 years STANDARD_DEVIATION 11 | 36 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 12 participants | 7 participants | 9 participants | 28 participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 32 | 22 / 31 | 18 / 28 |
| serious Total, serious adverse events | 0 / 32 | 0 / 31 | 1 / 28 |
Outcome results
Primary
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.
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SLCO1B1 Group 1 | Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 1.09 ng*hr/ml |
| SLCO1B1 Group 2 | Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 1.59 ng*hr/ml |
| SLCO1B1 Group 3 | Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 1.75 ng*hr/ml |
Comparison: Relative change data were compared between SLCO1B1 diplotype groups using one-way ANOVA (with post-hoc Bonferroni tests).p-value: 0.43ANOVA
Primary
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.
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SLCO1B1 Group 1 | Relative Change in Pravastatin Maximum Plasma Concentration (Cmax) | 1.11 ng/ml |
| SLCO1B1 Group 2 | Relative Change in Pravastatin Maximum Plasma Concentration (Cmax) | 1.69 ng/ml |
| SLCO1B1 Group 3 | Relative Change in Pravastatin Maximum Plasma Concentration (Cmax) | 2.32 ng/ml |
p-value: 0.28ANOVA
Secondary
Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
Dosing interval of 24 hours
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 63 ng*h/ml | Standard Deviation 25.2 |
| SLCO1B1 Group 2 | Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 86.6 ng*h/ml | Standard Deviation 36.3 |
| SLCO1B1 Group 3 | Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 123.4 ng*h/ml | Standard Deviation 80.1 |
p-value: 0.22ANOVA
Secondary
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
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax) | 27.7 ng/ml | Standard Deviation 15.4 |
| SLCO1B1 Group 2 | Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax) | 33.3 ng/ml | Standard Deviation 17.1 |
| SLCO1B1 Group 3 | Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax) | 46.2 ng/ml | Standard Deviation 38.6 |
p-value: 0.67ANOVA
Secondary
Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
Dosing interval of 24 hours
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 68.4 ng*h/ml | Standard Deviation 37.3 |
| SLCO1B1 Group 2 | Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 106.8 ng*h/ml | Standard Deviation 47.9 |
| SLCO1B1 Group 3 | Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 145.7 ng*h/ml | Standard Deviation 36.9 |
p-value: 0.006ANOVA
Secondary
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
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax) | 30.1 ng/ml | Standard Deviation 19.7 |
| SLCO1B1 Group 2 | Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax) | 42.4 ng/ml | Standard Deviation 23 |
| SLCO1B1 Group 3 | Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax) | 52.8 ng/ml | Standard Deviation 11.6 |
p-value: 0.08ANOVA
Other Pre-specified
Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
AUC of darunavir over a 12-hour dosing interval.
Time frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 58552 ng*h/ml | Standard Deviation 29442 |
| SLCO1B1 Group 2 | Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 63679 ng*h/ml | Standard Deviation 16985 |
| SLCO1B1 Group 3 | Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 60156 ng*h/ml | Standard Deviation 13909 |
p-value: 0.66ANOVA
Other Pre-specified
Darunavir Maximum Plasma Concentration (Cmax)
Cmax of darunavir over a 12-hour dosing interval
Time frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Darunavir Maximum Plasma Concentration (Cmax) | 7770 ng/ml | Standard Deviation 3483 |
| SLCO1B1 Group 2 | Darunavir Maximum Plasma Concentration (Cmax) | 8047 ng/ml | Standard Deviation 2023 |
| SLCO1B1 Group 3 | Darunavir Maximum Plasma Concentration (Cmax) | 7789 ng/ml | Standard Deviation 1467 |
p-value: 0.85ANOVA
Other Pre-specified
Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
AUC of ritonavir over a 12-hour dosing interval.
Time frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 5239 ng*hr/ml | Standard Deviation 3835 |
| SLCO1B1 Group 2 | Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 7178 ng*hr/ml | Standard Deviation 3520 |
| SLCO1B1 Group 3 | Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval | 7907 ng*hr/ml | Standard Deviation 3618 |
p-value: 0.11ANOVA
Other Pre-specified
Ritonavir Maximum Plasma Concentration (Cmax)
Cmax of ritonavir over a 12-hour dosing interval
Time frame: 0,1, 2, 3, 4, 5, 6, 8, 12 hours post-dose
Population: The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SLCO1B1 Group 1 | Ritonavir Maximum Plasma Concentration (Cmax) | 844 ng/ml | Standard Deviation 708 |
| SLCO1B1 Group 2 | Ritonavir Maximum Plasma Concentration (Cmax) | 1143 ng/ml | Standard Deviation 649 |
| SLCO1B1 Group 3 | Ritonavir Maximum Plasma Concentration (Cmax) | 1279 ng/ml | Standard Deviation 748 |
p-value: 0.15ANOVA