Darunavir/Ritonavir and Rosuvastatin Pharmacokinetic Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effects of Darunavir Plus Ritonavir on the Pharmacokinetics and Pharmacodynamics of Rosuvastatin

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: darunavir, ritonavir, rosuvastatin
* Drug: rosuvastatin, darunavir, ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Absence of HIV-1/HIV-2 infection as documented by a licensed ELISA test kit within 21 days prior to study entry. Male or female subjects, aged ≥ 18 and ≤ 60 years 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. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. Able to comply with protocol requirements. 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: 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. 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. Creatinine clearance of ≤ 60mL/min. Currently significant diarrhea, gastric stasis, or constipation that in the investigator's opinion could influence drug absorption or bioavailability. eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria, that in the opinion of the investigator would represent a contraindication to study enrollment. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the medications administered in the trial. 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. 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. 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. A positive pregnancy test or breast feeding at screening. Participation in an investigational drug trial within 90 days prior to the first intake of trial medication. Donation of blood or plasma within 60 days preceding the first trial-related blood drawing. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: B<br>Darunavir+ritonavir x 7 days; Rosuvastatin x 7 days; Combination x 7 days | Drug: darunavir, ritonavir, rosuvastatin<br>* 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<br>* Other names: Crestor;|
| Active Comparator: A<br>Rosuvastatin x 7 days; darunavir+ritonavir x 7 days; Combination x 7 days | Drug: rosuvastatin, darunavir, ritonavir<br>* 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<br>* Other names: Crestor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Rosuvastatin |  | 7 days | 
| AUC of Rosuvastatin |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 45 days | 
| 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 | 45 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, dyslipidemia, statins, protease inhibitors