Darunavir/Ritonavir and Rosuvastatin Pharmacokinetic Study

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: darunavir, ritonavir, rosuvastatin; Drug: rosuvastatin, darunavir, ritonavir

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati AIDS Clinical Trials Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: B; Darunavir+ritonavir x 7 days; Rosuvastatin x 7 days; Combination x 7 days	Drug: darunavir, 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; Other Names: Crestor; Prezista; Norvir
Active Comparator: A; Rosuvastatin x 7 days; darunavir+ritonavir x 7 days; Combination x 7 days	Drug: rosuvastatin, 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; Other Names: Crestor; Prezista; Norvir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Investigators: Principal Investigator: Carl J Fichtenbaum, MD, University of Cincinnati

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: April 20, 2009
• First Submitted That Met QC Criteria: April 21, 2009
• First Posted (Estimate): April 22, 2009

Study Record Updates

• Last Update Posted (Actual): February 11, 2022
• Last Update Submitted That Met QC Criteria: January 19, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: HIV; statins; dyslipidemia; protease inhibitors
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Rosuvastatin Calcium; Darunavir
• Other Study ID Numbers: IDC 40