Efavirenz and Ritonavir on Human Brian P-Glycoprotein (dLOP)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01668147
First received: July 30, 2012
Last updated: December 9, 2013
Last verified: December 2013

July 30, 2012
December 9, 2013
August 2012
June 2014   (final data collection date for primary outcome measure)
cerebral [11C]dLop distribution volume [ Time Frame: approximately 3 months ] [ Designated as safety issue: No ]
blood tests and PET data analysis and interpretation.
Same as current
Complete list of historical versions of study NCT01668147 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Efavirenz and Ritonavir on Human Brian P-Glycoprotein
Influence of Efavirenz and Ritonavir on Human Brain P-Glycoprotein Activity Using PET Imaging

The purpose of this research study is to determine the effects of ritonavir and efavirenz on the activity of P-glycoprotein in human brain.

Screening

Health self-assessment and undergo a medical history and physical examination, including a structured interview to screen for history of medical conditions, fasting blood glucose and HIV blood tests, urine HCG pregnancy test for women of childbearing potential will be performed within 24hr of study drug administration

Study visits Subjects will be studied on three occasions, with a washout between sessions. Sessions 1: Control (no pretreatment) - intravenous administration of 10 - 14 mCi of [11C] desmethyl-loperamide (dLop) with PET/CT imaging Session 2: Pretreatment with oral ritonavir for 3 days followed by intravenous administration of 10 - 14 mCi of [11C]dLOP with PET/CT imaging Session3: Pretreatment with oral efavirenz for 14 days followed by intravenous administration of 10 - 14 mCi of [11C]dLOP with PET/CT imaging

PreStudy Period Subjects who are potential candidates for the study will be educated as to the study procedures, benefits, and potential risks. They will fill out a health self-assessment and undergo a medical history and physical examination, including a structured interview to screen for history of medical conditions. Each subject who qualifies for entry into the study on the basis of inclusion/exclusion criteria, prestudy evaluations and completion of an informed consent will be assigned the next available patient number. This indicates enrollment in the study. Weight will be recorded. All enrolled subjects will undergo screening fasting blood glucose and HIV blood tests. Subjects are excluded if fasting glucose >110mg/dl (because ritonavir and efavirenz can cause glucose intolerance) or if they are HIV seropositive (since monotherapy can cause HIV resistance). Blood will be obtained for CYP3A and P-gp genotyping.

Study Period Subjects will be studied in Washington University's Center for Clinical Imaging Research (CCIR) following admission to the Clinical Research Unit for arterial (blood sampling) and peripheral venous catheter ([11C] dLop injection) insertion. Each study day will consist of an approximately 4-5 hr stay at WU Medical Center scanning, drug dosing, blood sampling and observation. Female subjects of childbearing potential will be asked to provide a urine sample for pregnancy testing on the morning of study visits. Subjects will have standard monitoring while in the scanner.

Subjects will be required to refrain from: 1) alcohol and caffeine for 24 hr prior to and during study days, 2) food/liquids after midnight the day prior to each drug administration, 3) any non-study medications (including over the counter and/or herbal) for 3 days prior to any study visit, without prior approval from the study doctor.

A blood sample is obtained once to isolate DNA and determine CYP3A and P-gp genotype. Subjects are not informed of the results of genotype tests because they are experimental, and because there are no conclusive links between genotypes and the risk of disease or adverse events from drug therapy.

Before the study sessions start, a small intravenous (IV) catheter (small plastic tube) will be placed in the patients arm or hand. This catheter will be used to inject the [11C]dLOP. IV fluids will be given throughout the study days. A second catheter will be inserted into the wrist artery for drawing periodic blood samples during the study days.

We will use Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), two sophisticated imaging technologies to take pictures of the amount and location of [11C]dLOP in the brain at all three study visits.

MRI Scan:

The MRI will be conducted on the same day as the first PET. The MRI scanner will take pictures of the brain. An MRI scanner uses simple radio waves to create these pictures. The participant will be positioned on their back on the scanner bed and made to feel as comfortable as possible. The scanner bed will be moved inside a large tube so that the participants head and chest are inside, but they will be able to see out into the room by their feet. During the scan, participants will hear loud, rhythmic knocking sounds. Participants ears will be covered to keep the noise to a minimum. It may also be possible to listen to music through headphones during the scan. There is a speaker and a microphone in the scanner so that participants can talk to the MRI technician if there is something they need. Once the scan is begun, participants will need to lie still since movement will ruin the images of their brain. No intravenous contrast will be given to participants during the MRI scan. This procedure will take up to 30 minutes.

PET/CT Scan:

The PET/CT scanner uses a special radiation detection camera to produce pictures of the amount of [11C]dLOP in participants brain using a small amount of radioactive [11C]dLop. For each PET/CT scan, participants will be asked to lie still with their head in a padded holder inside the scanner. A warm, plastic mask with large eyeholes will be placed across the top of the participants face. The mask hardens as it cools and will help participants remember to keep their head still while in the scanner. The PET scan procedure will take approximately two hours from start to finish this includes set-up and approximately 60 minutes for scanning).

At all 3 study visits [11C]dLop in tracer doses up to 5.8 ug is administered intravenously in the PET scanning suite, and a series of PET images will be taken. Blood samples will be obtained from the arterial catheter during the exam to evaluate plasma concentrations of the [11C]dLop. Approximately 30 samples will be collected. Each sample will be 1ml. The total amount of blood collected during this scan is approximately 2 tablespoons.

Visit 1 is a control visit and will not include pretreatment. Patients will receive [11C] dLop intravenously, a PET/CT scan, MRI and blood sampling as described above.

Visit 2 will occur 3-30 days after Visit 1. Participants will take Ritonavir by mouth for 2 days before the PET/CT session listed above. On the study day participants will take Ritonavir 400 mg in the morning before the scan. Participants will then receive [11c] dLop, a PET/CT scan and blood sampling as described above.

Visit 3 will occur 2-4 weeks after Visit 2. Participants will take Efavirenz 600 mg by mouth every night for 14 days prior to the study day. On the study day participants will have receive [11c] dLop, a PET/CT scan and blood sampling as described above.

Participants will be monitored by a member of the research team during your scans.

Interventional
Not Provided
Intervention Model: Single Group Assignment
Masking: Open Label
Drug Effects
  • Drug: [11c] desmethyl-loperamide (dLop)
    intravenous administration of 10-14 mCi of [11C] desmethyl-loperamide (dLop) with PET/CT imaging
    Other Name: DESMETHYL LOPERAMIDE
  • Drug: Ritonavir
    Pretreatment with oral ritonavir for 3 days followed by intravenous administration of 10-14 mCi of [11C]dLop with PET/CT imaging
    Other Name: Kaletra
  • Drug: Efavirenz
    Pretreatment with oral efavirenz for 14 days followed by intravenous administration of 10-14 mCi of [11C]dLop with PET/CT imaging
    Other Name: Sustiva,Atripla
Experimental: study arm
Sessions 1: Control (no pretreatment) - intravenous administration of 10-14 mCi of [11C] desmethyl-loperamide (dLop) with PET/CT imaging Session 2: Pretreatment with oral ritonavir for 3 days followed by intravenous administration of 10-14 mCi of [11C]dLop with PET/CT imaging Session3: Pretreatment with oral efavirenz for 14 days followed by intravenous administration of 10-14 mCi of [11C]dLop with PET/CT imaging
Interventions:
  • Drug: [11c] desmethyl-loperamide (dLop)
  • Drug: Ritonavir
  • Drug: Efavirenz
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
8
August 2016
June 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Male or non-pregnant female, 18-40 yr old
  • Good general health with no remarkable medical conditions
  • BMI < 33
  • Provide informed consent

Exclusion Criteria:

  • Known history of liver or kidney disease
  • History of major medical conditions
  • HIV seropositive
  • Fasting blood glucose > 110 mg/dl
  • Family history of type 2 diabetes
  • Use of prescription or non prescription medications, herbals or foods known to be metabolized by or altering P-glycoprotein or CYP3A activity (hormonal birth control medications are acceptable if alternative means of contraception are used)
  • Females who are pregnant or nursing
  • Females taking hormonal contraceptives who are unwilling to use alternative means of contraception
  • Contraindications to MRI
  • Contraindications to PET scanning
Both
18 Years to 40 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01668147
201205135
No
Washington University School of Medicine
Washington University School of Medicine
Not Provided
Principal Investigator: Evan Kharasch, MD, PhD. Washington University School of Medicine
Washington University School of Medicine
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP