HIV Infections
Conditions
Keywords
HIV, dyslipidemia, statins, protease inhibitors
Brief summary
This is a phase I, open-label, controlled drug interaction study to determine the effects of darunavir plus ritonavir on the pharmacokinetics of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, in HIV-1-seronegative subjects.
Detailed description
Twelve HIV-negative healthy volunteers will be randomized to one of two groups. Group 1 would receive rosuvastatin 10mg daily (Treatment A) in interval 1 for 7 days, followed by a washout period of at least 7 days. In interval 2, darunavir/ritonavir 600/100mg bid (Treatment B) would be administered for 7 days, followed by another 7 day washout period. Lastly, in interval 3 subjects will administer darunavir/ritonavir and rosuvastatin (Treatment C) for total of 7 days. Group 2 will administer Treatment B in interval 1 for 7 days, followed by a washout period of 7 days, then treatment A in interval 2 for 7 days followed by another 7 day washout period. Group 2 would then co-administer rosuvastatin and darunavir/ritonavir for the last 7 days. Intensive PK sampling will be performed on day 7, 21 and 35 following a meal.
Interventions
DRUGdarunavir, ritonavir, rosuvastatin
darunavir 600 mg twice daily for 7 days ritonavir 100 mg twice daily for 7 days rosuvastatin 10 mg once daily for 7 days Combination of all three drugs for 7 days
DRUGrosuvastatin, darunavir, ritonavir
rosuvastatin 10 mg daily for 7 days; darunavir 600 mg twice daily for 7 days with ritonavir 100 mg twice daily for 7 days; Combination of all three for 7 days
Sponsors
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Absence of HIV-1/HIV-2 infection as documented by a licensed ELISA test kit within 21 days prior to study entry. 2. Male or female subjects, aged ≥ 18 and ≤ 60 years 3. Weight ≥50 kg and a Body Mass Index (\[BMI\], weight in kg divided by the square of height in meters) ≥18.0 and ≤ 35.0 kg/m2. Refer to Appendix I. 4. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 5. Able to comply with protocol requirements. 6. Healthy on the basis of a medical evaluation that reveals the absence of any clinically relevant abnormality and includes a physical examination, medical history, vital signs, and the results of blood tests and a urinalysis carried out at screening.
Exclusion criteria
1. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which in the investigator's opinion would compromise subject's safety and/or compliance with the trial procedures. 2. Currently active significant gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease, that in the opinion of the investigator would represent a contraindication to study enrollment. 3. Creatinine clearance of ≤ 60mL/min. 4. Currently significant diarrhea, gastric stasis, or constipation that in the investigator's opinion could influence drug absorption or bioavailability. 5. eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria, that in the opinion of the investigator would represent a contraindication to study enrollment. 6. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the medications administered in the trial. 7. History of significant drug allergy such as, but not limited to, sulphonamides and penicillins. Prezista is a sulphonamide. The potential for cross-sensitivity between drugs in the sulphonamide class and Prezista in HIV-negative subjects is unknown. 8. Use of concomitant medication, including investigational, prescription, and over-the-counter products and dietary supplements with the following exceptions: aspirin, acetaminophen, anti-histamines such as diphenhydramine, inhalers for asthma, daily multivitamins, mineral supplements and hormonal oral contraceptives. Concomitant medication other than those listed above must have been discontinued at least 7 days before study entry. 9. Female subjects of childbearing potential without use of effective nonhormonal birth control methods, or not willing to continue practicing these birth control methods for at least 30 days after the end of the treatment period; Note: Estrogen-based hormonal contraception may not be reliable when taking Prezista, therefore to be eligible for this trial, women of childbearing potential should either: * use a double barrier method to prevent pregnancy (i.e., using a condom with either diaphragm or cervical cap); * use non-estrogen hormonal based contraceptives in combination with a barrier contraceptive (i.e., male condom, diaphragm or cervical cap, or female condom); * use a intrauterine device in combination with a barrier contraceptive (i.e., male condom, diaphragm or cervical cap, or female condom); * be not sexually active, or have a vasectomized partner (confirmed sterile). Women with tubal ligation are required to use one non-hormonal contraceptive method. Women who are postmenopausal for at least 2 years, and women with total hysterectomy are considered of non-childbearing potential. 10. A positive pregnancy test or breast feeding at screening. 11. Participation in an investigational drug trial within 90 days prior to the first intake of trial medication. 12. Donation of blood or plasma within 60 days preceding the first trial-related blood drawing. 13. Subjects with the following laboratory abnormalities at screening as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS grading table) and in accordance with the normal ranges of the trial clinical laboratory: * serum creatinine grade 1 or greater (≥ 1.1 x upper limit of laboratory normal range \[ULN\]); * lipase or pancreatic amylase grade 1 or greater (≥ 1.1 x 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), * any other laboratory abnormality of grade 2 or above
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cmax of Rosuvastatin | 7 days |
| AUC of Rosuvastatin | 7 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir. | 45 days | Geometric mean of the Concentration minimum of darunavir and ritonavir in the presence and absence of rosuvastatin. |
| To Compare the Change in Low-density Lipoprotein (LDL) Cholesterol With Rosuvastatin Therapy Alone, Darunavir/Ritonavir Therapy Alone and With the Co-administration of Rosuvastatin and Darunavir/Ritonavir. | 45 days | LDL values |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the community between September 2008 and March 2009
Pre-assignment details
1 subject was excluded based upon elevated triglyceride level prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| B-Darunavir+Ritonavir Initial Arm Darunavir+ritonavir x 7 days; Rosuvastatin x 7 days; Combination x 7 days | 8 |
| A-Rosuvastatin Initial Arm Rosuvastatin x 7 days; darunavir+ritonavir x 7 days; Combination x 7 days | 9 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | A-Rosuvastatin Initial Arm | B-Darunavir+Ritonavir Initial Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 8 Participants | 17 Participants |
| Age, Continuous | 28 years STANDARD_DEVIATION 10 | 28 years STANDARD_DEVIATION 11 | 28 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 9 participants | 8 participants | 17 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 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 | 6 / 15 | 4 / 14 | 4 / 12 |
| serious Total, serious adverse events | 0 / 15 | 0 / 14 | 0 / 12 |
Outcome results
Primary
AUC of Rosuvastatin
Time frame: 7 days
Population: Analysis of 12 subjects who completed all 3 PK visits
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Rosuvastatin | AUC of Rosuvastatin | 108.96 ng*hr/mL |
| Rosuvastatin-Darunavir-Ritonavir | AUC of Rosuvastatin | 161.24 ng*hr/mL |
Primary
Cmax of Rosuvastatin
Time frame: 7 days
Population: Analysis of 12 subjects who completed all 3 PK visits
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Rosuvastatin | Cmax of Rosuvastatin | 6.70 ng/mL |
| Rosuvastatin-Darunavir-Ritonavir | Cmax of Rosuvastatin | 16.32 ng/mL |
Secondary
To Compare the Change in Low-density Lipoprotein (LDL) Cholesterol With Rosuvastatin Therapy Alone, Darunavir/Ritonavir Therapy Alone and With the Co-administration of Rosuvastatin and Darunavir/Ritonavir.
LDL values
Time frame: 45 days
Population: Individuals taking medications with measurements of LDL
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rosuvastatin | To Compare the Change in Low-density Lipoprotein (LDL) Cholesterol With Rosuvastatin Therapy Alone, Darunavir/Ritonavir Therapy Alone and With the Co-administration of Rosuvastatin and Darunavir/Ritonavir. | 85 mg/dL |
| Rosuvastatin-Darunavir-Ritonavir | To Compare the Change in Low-density Lipoprotein (LDL) Cholesterol With Rosuvastatin Therapy Alone, Darunavir/Ritonavir Therapy Alone and With the Co-administration of Rosuvastatin and Darunavir/Ritonavir. | 115 mg/dL |
| Rosuvastatin+Darunavir/Ritonavir | To Compare the Change in Low-density Lipoprotein (LDL) Cholesterol With Rosuvastatin Therapy Alone, Darunavir/Ritonavir Therapy Alone and With the Co-administration of Rosuvastatin and Darunavir/Ritonavir. | 80 mg/dL |
Secondary
To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir.
Geometric mean of the Concentration minimum of darunavir and ritonavir in the presence and absence of rosuvastatin.
Time frame: 45 days
Population: Participants taking all three medications
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Rosuvastatin | To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir. | Darunavir Cmin with Rosuvastatin | 2744 ng/mL |
| Rosuvastatin | To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir. | Darunavir Cmin absent Rosuvastatin | 3235 ng/mL |
| Rosuvastatin | To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir. | Ritonavir Cmin absent Rousuvastatin | 194 ng/mL |
| Rosuvastatin | To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir. | Ritonavir Cmin with Rousuvastatin present | 148 ng/mL |