Clinical trial NCT00571961
Conditions: HIV Infections
Keywords: HIV Pharmacokinetics Buprenorphine Kaletra HIV Seronegativity
Sponsor: Yale University
Start date: 2007-01-01; Completion date: 2008-08-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief 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.

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).

Arms: arm 1: 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.
Interventions: intervention 1: Kaletra (lopinavir/ritonavir) intervention 2: buprenorphine intervention 3: Clinical evaluations/Blood draws
Intervention descriptions: intervention 1: 4 tablets, once a day (800 mg/dose) on Days 2 through 14 of this study intervention 2: Buprenorphine will be obtained through prescription at the subject's drug treatment program. intervention 3: Physical examinations, vital sign measurements, 12-lead electrocardiogram (ECG), clinical laboratory evaluations (blood chemistry and blood counts), PK blood draws.

Protocol documents: