HIV Infections
Conditions
Keywords
HIV, Pharmacokinetics, Buprenorphine, Tipranavir, HIV Seronegativity
Brief summary
The main purpose of this study is to examine the effect of tipranavir combined with ritonavir, medications for the treatment of HIV-infection, on buprenorphine/naloxone (BUP) in people who have been receiving the same dose of buprenorphine/naloxone for at least 3 weeks before study entry.
Detailed description
A large number of people with HIV-infection obtained HIV through injection drug use. Some of these people are currently being treated with buprenorphine/naloxone (BUP) for their addiction and with medications for HIV infection. Tipranavir is a medication that was recently approved by the Food and Drug Administration (FDA) for the treatment of HIV-infection. Tipranavir is given in combination with another HIV medication, ritonavir. Tipranavir acts by making it more difficult for the virus that causes AIDS to multiply and cause more damage to the immune system. Ritonavir acts by increasing the amount of tipranavir available to fight HIV. Earlier studies looking at the combination of BUP and HIV medications have shown that BUP and some HIV medications act differently when taken together. It is important to learn if taking BUP and HIV medications together results in changes in the blood level of either medication. If the HIV medication decreases the level of BUP in the blood, an individual taking BUP and HIV medications may experience symptoms of withdrawal (dope sickness), even while taking their usual dose of BUP. On the other hand, if BUP decreases the amount of HIV medication in the blood, then the HIV medication may be less effective in controlling HIV infection. It is therefore important to learn if tipranavir/ritonavir and BUP will affect each other when taken together. In order to learn about the effects of BUP on tipranavir/ritonavir, we will need to measure the amount of BUP in your blood for 24 hours after you have taken tipranavir/ritonavir and BUP together and then compare that to the amount of BUP in your blood when you are not taking tipranavir/ritonavir.
Interventions
DRUGBuprenorphine, Tipranavir and ritonavir
After determining buprenorphine/naloxone pharmacokinetics over a 24-hour period, tipranavir/ritonavir and buprenorphine/naloxone will be coadministered for 7 days.
Sponsors
Boehringer Ingelheim
Yale University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Buprenorphine/naloxone (BUP/NAL) users (taking 16/4 mg sublingually daily) for at least 3 weeks deemed by the investigator to have acceptable medical history, physical examination, 12 lead electrocardiogram, and clinical laboratory evaluations consistent with BUP maintenance will be eligible to participate in the study. * Subjects who meet the criteria of opiate dependence, are enrolled in long-term BUP maintenance therapy, and have been on a stable dose of BUP/NAL for at least 3 weeks. * Body weight \> 60 kg for males and \> 40 kg for females * Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive. BMI = weight (kg)/ \[height(m)\]2. * Male or females, ages \> 18 to \< 60 years. * Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be on adequate non-hormonal contraception to avoid pregnancy. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Study Day 1.
Exclusion criteria
* History or current evidence of any significant acute or chronic medical illness that, within the investigator's discretion, would interfere with the conduct or interpretation of the study. * History of acute or chronic pancreatitis. * History of uncontrolled chronic medical illness which could adversely affect the subject's adherence to study protocol or affect patient safety in the opinion of the investigator * Use of any medication thought to significantly alter the metabolism of tipranavir, ritonavir, Buprenorphine or naloxone. * History of any hemolytic disorders (including drug-induced hemolysis). * Proven or suspected acute hepatitis at the time of study entry. * Chronic liver disease with Childs-Pugh Class B or C staging * Current or recent (within 3 months) gastrointestinal disease which would interfere with the conduct or interpretation of the study. * Any major surgery within 4 weeks of enrollment. Minor surgical procedures requiring local anesthesia are exceptions. * Any gastrointestinal surgery that could impact upon the absorption of study drug. * Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within 4 weeks of enrollment. * Blood transfusion within 4 weeks of enrollment. * Inability to tolerate oral medication. * Inability to tolerate venipuncture and/or absence of secure venous access. * Inability to refrain from smoking during in-residence period * Known or suspected HIV infection (subjects who are found to be positive upon screen for HIV will be excluded). * Known active drug or alcohol abuse, which in the opinion of the investigator makes study participation to completion unlikely. * Any other sound medical, psychiatric and/or social reason as determined by the Investigator. * Evidence of organ dysfunction or any clinically relevant (as determined by the investigator) deviations from the norms observed in a buprenorphine/naloxone treated population in physical examination, vital signs, ECG or clinical laboratory determinations. * Ingestion of alcohol within 24 hours prior to the dose of study medication * Positive breathalyzer alcohol test, or positive urine screen for barbiturates, benzo-diazepines, amphetamines, THC, cocaine or opiates other than buprenorphine/naloxone. * Positive blood screen for HIV antibody. * Subjects with AST, ALT or bilirubin \> 2.5X the upper limit of normal. * Hemoglobin \< 9 g/dL, and platelet count \< 75, 000/mm3. * Positive serum or urine for HCG. * History of any significant drug allergy, drug rash or sensitivity to any class of drugs relevant to the study drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of BUP/NLX With TPV/r (h*ng/mL) | 10 days | Non-compartmental methods were used for pharmacokinetic analysis. The area under the plasma drug concentration-time curve was estimated by linear-log trapezoidal rule at 24-hrs. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from buprenorphine maintenance treatment in New Haven over a year period. Subjects were hospitalized at baseline to be stabilized on buprenorphine/naloxone (BUP/NLX) therapy.
Pre-assignment details
There were no pre-assignment exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Tipranavir/Ritonavir (500mg/200mg) | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Tipranavir/Ritonavir (500mg/200mg) |
|---|---|
| Age, Continuous | 44 years FULL_RANGE 10 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Area Under the Curve of BUP/NLX With TPV/r (h*ng/mL)
Non-compartmental methods were used for pharmacokinetic analysis. The area under the plasma drug concentration-time curve was estimated by linear-log trapezoidal rule at 24-hrs.
Time frame: 10 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Tipranavir/Ritonavir (500mg/200mg) | Area Under the Curve of BUP/NLX With TPV/r (h*ng/mL) | 43.7 h*ng/mL |