HIV InfectionsNCT00571961
Pharmacokinetic Interactions Between Buprenorphine and Kaletra (Lopinavir/Ritonavir)
A study testing Kaletra (lopinavir/ritonavir), buprenorphine and Clinical evaluations/Blood draws in people with HIV Infections, run by Yale University at 1 site in United States.
Trial summary
The main purpose of this protocol is to study the effect of an HIV medication, Kaletra (lopinavir/ritonavir), on buprenorphine in non-HIV infected people who have been receiving the same dose of buprenorphine for at least 3 weeks. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- HIV Infections
- What is being tested?
- Kaletra (lopinavir/ritonavir), buprenorphine and Clinical evaluations/Blood draws
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2007to Aug 2008
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Chronic BUP users enrolled in BUP program, receiving BUP for at least 3 months and on a stable BUP dose for at least 3 weeks.
- Acceptable medical history, physical examination, 12 lead electrocardiogram, and clinical laboratory evaluations consistent with BUP maintenance
- 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 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 65 years.
- Women of childbearing potential (WOCBP) must not be nursing, pregnant and 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.
Who cannot join
- Sex and Reproductive Status Exceptions
- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks before and after the study.
- WOCBP using a prohibited contraceptive method (oral, injectable, or implantable hormonal agents)
- Women who are pregnant or breastfeeding
- Women with a positive pregnancy test on enrollment or prior to study drug administration.
- Medical History and Concurrent Diseases
Show all 36Show fewer
- 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 nephrolithiasis
- 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 Kaletra, Buprenorphine or naloxone.
- History of any hemolytic disorders (including drug-induced hemolysis).
- Proven or suspected acute hepatitis at the time of study entry.
- 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-patient 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.
- Physical and Laboratory Test Findings
- Evidence of organ dysfunction or any clinically relevant deviations from the norms observed in a buprenorphine 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, benzodiazepines, amphetamines or opiates other than buprenorphine.
- Positive blood screen for HIV antibody.
- QTc interval >450 msec for males or >470 msec for females.
- Second or third-degree AV block.
- Creatinine clearance(as estimated by method of Cockcroft and Gault) less than 80 mL/min.
- CLcr=0.85(females only)x(140-age)x weight(kg)
- serum creatinine(mg/dL)x 72
- Subjects with bilirubin >2 mg/dL, serum albumin <2.5 g/dL and ascites, AST and ALT >3 times ULN, hemoglobin <9 g/dL, and platelet count <75,000/mm3.
- Positive serum or urine for HCG.
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale University School of Medicine
New Haven, Connecticut, 06520
About this study
The main purpose of this protocol is to study the effect of an HIV medication, Kaletra (lopinavir/ritonavir), on buprenorphine in non-HIV infected people who have been receiving the same dose of buprenorphine for at least 3 weeks.
Study Hypothesis:
Kaletra (lopinavir/ritonavir) will increase buprenorphine plasma levels without any significant clinical effect on the subject or need for dose adjustment.
Read the detailed description
Buprenorphine (BUP) is a partial opiate agonist dosed sublingually for both supervised opiate withdrawal and maintenance for opiate dependence. Until recently, methadone has been the mainstay of pharmacological treatment for opiate-dependent persons with HIV infection. In October, 2002, buprenorphine (BUP) was approved for opiate maintenance and can be prescribed by primary care physicians. It is anticipated that many HIV specialists will begin prescribing BUP for their HIV+ patients on ARVs with a history of opiate dependence. This will continue to increase in importance as a method of treatment for this patient population for the following reasons: 1) Multiple federal programs are working to encourage the use of BUP in primary care, especially HIV primary care, settings. The goal of these programs is to increase opiate treatment slots across the country. 2) Many methadone programs have wait lists or regulations (e.g., daily dosing) which may not be possible for some patients. BUP, with its flexibility in dosing and ease of use, will increasingly become a first line in the treatment of opioid dependence.
Buprenorphine administration carries the theoretical risk of drug interactions with respect to both inhibition or induction of BUP as well as similar effects on medications co-administered with BUP. Interactions may lead to under or overdosing of buprenorphine and/or antiretroviral agents with resultant adverse clinical consequences.
Buprenorphine's effects on Kaletra and other ARVs cannot be predicted based on prior experience with methadone because BUP metabolism appears to differ from methadone in terms of its substrate and effects on cytochrome P450.
Limited information currently exists regarding interactions between HIV therapeutic agents and buprenorphine. Similar to buprenorphine, the protease inhibitors, and NNRTIs are metabolized primarily via the CYP3A4 isozyme of the cytochrome P450 system. The extent to which methadone levels decrease with induction of cytochrome P450 isoenzymes has been correlated clinically with severity of symptoms of withdrawal. Similar studies with buprenorphine are not yet available. Interactions between buprenorphine and antiretroviral agents may complicate the management of HIV disease when these medications are coadministered. In a small sample study, there was no increase in buprenorphine dosing required when co-administered with Sustiva. However, in one study with liver microsomes, ritonavir inhibited the metabolism of buprenorphine at CYP 3A4, but the clinical significance of this inhibition could not be demonstrated. It is well known that in vitro and in vivo studies do not fully correlate with one another and empiric pharmacologic interaction studies in human subjects are necessary.
The treatment of opiate addiction is a complicated and labor intensive practice. This study will require the use of Kaletra alone in HIV negative opiate dependent patients. This is critical to ascertain the reality of both objective data (levels of buprenorphine and lopinavir), as well as valid subjective symptoms of opiate withdrawal (symptoms that addicts have previously experienced and can more readily communicate).
- Conditions
- HIV Infections
- Being tested
- Kaletra (lopinavir/ritonavir), buprenorphine, Clinical evaluations/Blood draws
- Keywords
- HIV, Pharmacokinetics, Buprenorphine, Kaletra, HIV Seronegativity
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Kaletra (lopinavir/ritonavir)Drug
4 tablets, once a day (800 mg/dose) on Days 2 through 14 of this study
buprenorphineDrug
Buprenorphine will be obtained through prescription at the subject's drug treatment program.
Clinical evaluations/Blood drawsOther
Physical examinations, vital sign measurements, 12-lead electrocardiogram (ECG), clinical laboratory evaluations (blood chemistry and blood counts), PK blood draws.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | HIV negative subjects currently enrolled in a long-term buprenorphine maintenance therapy program for at least 3 months who have been on stable dose of buprenorphine for at least 3 weeks will be admitted to the General Clinical Research Center (GCRC) for pharmacokinetic (PK) blood draws at intervals over a 24-hour period. Subjects will then receive Kaletra and buprenorphine coadministered for 14 days. Subjects will be admitted to the GCRC for a second PK sampling day. Receives: Drug: Kaletra (lopinavir/ritonavir); Drug: buprenorphine; Other: Clinical evaluations/Blood draws |
What is being measured
The primary outcome is the main question the study is designed to answer.
Buprenorphine Area Under the Curve With LPV/r (ng/mL*hr)
Pharmacokinetic parameters were determined by use of non compartmental methods. The area under the plasma concentration versus time curve was determined by use of the trapezoidal rule and measured over a 24-hr time period.
Measured: 15 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2007 (estimated)
- Study startJan 2007
- Primary completionAug 2008
- Study completionAug 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Abbott
- Responsible party
- Principal investigator, R. Douglas Bruce, MD, MA, Yale University
- Investigators
- Robert D Bruce, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00571961
- Sponsor's protocol ID
- 0511000791
- Other IDs
- M118687
- Status last verified
- Oct 2012
- First submitted
- 11 Dec 2007
- Last updated
- 21 Nov 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Bruce RD, Altice FL, Moody DE, Morse GD, Andrews L, Lin SN, Fang WB, Ma Q, Friedland GH. Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir. J Acquir Immune Defic Syndr. 2010 Aug;54(5):511-4. doi: 10.1097/qai.0b013e3181d3cad3.
PubMed 20672450
Study at a glance
From the registry record, last updated by the sponsor on 21 Nov 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic Interactions Between Buprenorphine and Kaletra (Lopinavir/Ritonavir)
- ClinicalTrials.gov ID
- NCT00571961
- Acronym / sponsor ID
- 0511000791
- Conditions
- HIV Infections
- Keywords
- HIV, Pharmacokinetics, Buprenorphine, Kaletra, HIV Seronegativity
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Abbott
- Study start
- Jan 2007
- Primary completion
- Aug 2008 (actual)
- Study completion
- Aug 2008 (actual)
- First posted
- 12 Dec 2007 (estimated)
- Results
- Posted 21 Nov 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The main purpose of this protocol is to study the effect of an HIV medication, Kaletra (lopinavir/ritonavir), on buprenorphine in non-HIV infected people who have been receiving the same dose of buprenorphine for at least 3 weeks.
Study Hypothesis:
Kaletra (lopinavir/ritonavir) will increase buprenorphine plasma levels without any significant clinical effect on the subject or need for dose adjustment.
Detailed description
Buprenorphine (BUP) is a partial opiate agonist dosed sublingually for both supervised opiate withdrawal and maintenance for opiate dependence. Until recently, methadone has been the mainstay of pharmacological treatment for opiate-dependent persons with HIV infection. In October, 2002, buprenorphine (BUP) was approved for opiate maintenance and can be prescribed by primary care physicians. It is anticipated that many HIV specialists will begin prescribing BUP for their HIV+ patients on ARVs with a history of opiate dependence. This will continue to increase in importance as a method of treatment for this patient population for the following reasons: 1) Multiple federal programs are working to encourage the use of BUP in primary care, especially HIV primary care, settings. The goal of these programs is to increase opiate treatment slots across the country. 2) Many methadone programs have wait lists or regulations (e.g., daily dosing) which may not be possible for some patients. BUP, with its flexibility in dosing and ease of use, will increasingly become a first line in the treatment of opioid dependence.
Buprenorphine administration carries the theoretical risk of drug interactions with respect to both inhibition or induction of BUP as well as similar effects on medications co-administered with BUP. Interactions may lead to under or overdosing of buprenorphine and/or antiretroviral agents with resultant adverse clinical consequences.
Buprenorphine's effects on Kaletra and other ARVs cannot be predicted based on prior experience with methadone because BUP metabolism appears to differ from methadone in terms of its substrate and effects on cytochrome P450.
Limited information currently exists regarding interactions between HIV therapeutic agents and buprenorphine. Similar to buprenorphine, the protease inhibitors, and NNRTIs are metabolized primarily via the CYP3A4 isozyme of the cytochrome P450 system. The extent to which methadone levels decrease with induction of cytochrome P450 isoenzymes has been correlated clinically with severity of symptoms of withdrawal. Similar studies with buprenorphine are not yet available. Interactions between buprenorphine and antiretroviral agents may complicate the management of HIV disease when these medications are coadministered. In a small sample study, there was no increase in buprenorphine dosing required when co-administered with Sustiva. However, in one study with liver microsomes, ritonavir inhibited the metabolism of buprenorphine at CYP 3A4, but the clinical significance of this inhibition could not be demonstrated. It is well known that in vitro and in vivo studies do not fully correlate with one another and empiric pharmacologic interaction studies in human subjects are necessary.
The treatment of opiate addiction is a complicated and labor intensive practice. This study will require the use of Kaletra alone in HIV negative opiate dependent patients. This is critical to ascertain the reality of both objective data (levels of buprenorphine and lopinavir), as well as valid subjective symptoms of opiate withdrawal (symptoms that addicts have previously experienced and can more readily communicate).
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Kaletra (lopinavir/ritonavir), Drug: buprenorphine, Other: Clinical evaluations/Blood drawsHIV negative subjects currently enrolled in a long-term buprenorphine maintenance therapy program for at least 3 months who have been on stable dose of buprenorphine for at least 3 weeks will be admitted to the General Clinical Research Center (GCRC) for pharmacokinetic (PK) blood draws at intervals over a 24-hour period. Subjects will then receive Kaletra and buprenorphine coadministered for 14 days. Subjects will be admitted to the GCRC for a second PK sampling day. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Chronic BUP users enrolled in BUP program, receiving BUP for at least 3 months and on a stable BUP dose for at least 3 weeks.
- Acceptable medical history, physical examination, 12 lead electrocardiogram, and clinical laboratory evaluations consistent with BUP maintenance
- 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 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.
Key exclusion criteria (36 listed)
- Sex and Reproductive Status Exceptions
- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks before and after the study.
- WOCBP using a prohibited contraceptive method (oral, injectable, or implantable hormonal agents)
- Women who are pregnant or breastfeeding
- Women with a positive pregnancy test on enrollment or prior to study drug administration.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Kaletra (lopinavir/ritonavir)4 tablets, once a day (800 mg/dose) on Days 2 through 14 of this study | Drug | 1 |
| buprenorphineBuprenorphine will be obtained through prescription at the subject's drug treatment program. | Drug | 1 |
| Clinical evaluations/Blood drawsPhysical examinations, vital sign measurements, 12-lead electrocardiogram (ECG), clinical laboratory evaluations (blood chemistry and blood counts), PK blood draws. | Other | 1 |
Primary outcome
Buprenorphine Area Under the Curve With LPV/r (ng/mL*hr)
Time frame: 15 days
Pharmacokinetic parameters were determined by use of non compartmental methods. The area under the plasma concentration versus time curve was determined by use of the trapezoidal rule and measured over a 24-hr time period.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Nov 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 20672450Bruce RD, Altice FL, Moody DE, Morse GD, Andrews L, Lin SN, Fang WB, Ma Q, Friedland GH. Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir. J Acquir Immune Defic Syndr. 2010 Aug;54(5):511-4. doi: 10.1097/qai.0b013e3181d3cad3.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert D Bruce, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Kaletra (lopinavir/ritonavir), buprenorphine and Clinical evaluations/Blood draws in people with HIV Infections, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Nov 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Nov 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Buprenorphine Area Under the Curve With LPV/r (ng/mL*hr) (time frame: 15 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00571961, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Nov 2012.