Clinical trial NCT00885495: Darunavir/Ritonavir and Rosuvastatin Pharmacokinetic Study
Official title: The Effects of Darunavir Plus Ritonavir on the Pharmacokinetics and Pharmacodynamics of Rosuvastatin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: HIV
dyslipidemia
statins
protease inhibitors
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
First posted: 2009-04-22
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Cmax of Rosuvastatin
timeFrame: 7 days
measure: AUC of Rosuvastatin
timeFrame: 7 days
Secondary outcomes:
measure: To Investigate the Effect of Rosuvastatin on the Steady State Pharmacokinetics of Darunavir/Ritonavir.
timeFrame: 45 days
measure: 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.
timeFrame: 45 days
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: University of Cincinnati AIDS Clinical Trials Unit
state: Ohio
Study officials:
affiliation: University of Cincinnati
name: Carl J Fichtenbaum, MD
role: PRINCIPAL_INVESTIGATOR
References: