This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir (800/200 mg) in 12 HIV-negative subjects stable on buprenorphine/naloxone.

Compared to baseline vales, buprenorphine AUC (46.9 vs 46.2 ng.h/ml) and Cmax (6.54 vs 5.88 ng/ml) did not differ significantly after achieving steady state lopinavir/ritonavir.  Similar analyses of norbuprenorphine (the primary metabolite of buprenorphine) demonstrated no significant difference in AUC (73.7 vs 52.7 ng.h/ml); however, Cmax was significantly decreased (5.29 vs 3.11 ng/ml, P<0.05) after lopinavir/ritonavir administration.  Naloxone concentrations were unchanged for AUC (0.421 vs 0.374 ng.h/ml) and Cmax (0.186 vs 0.186 ng/ml).  Using standardised measures, no objective opioid withdrawal was observed.  The AUC and Cmin of lopinavir in this study did not differ significantly from historical controls (159.6 vs 171.3 ug.h/ml and 2.3 vs 1.3 ug/ml, respectively).

The addition of lopinavir/ritonavir to patients stable on buprenorphine/naloxone did not affect buprenorphine AUC or Cmax, but did decrease Cmax of norbuprenorphine.  Naloxone concentrations were similarly unchanged.  Pharmacodynamic responses indicate that the altered norbuprenorphine concentrations did not lead to opioid withdrawal.  Buprenorphine/naloxone and once-daily lopinavir/ritonavir can be coadministered safely without need for dosage modification.
Source: HIV-druginteractions.org

Pharmacokinetic interactions between buprenorphine/naloxone and once daily lopinavir/ritonavir

Reference:

Bruce RD et al. J Acquir Immune Defic Syndr, 2010, 54(5): 511-514

The effect of TMC278 (25 mg once daily) on the pharmacokinetics and pharmacodynamics of methadone was studied in 13 HIV negative volunteers stable on methadone maintenance therapy (60-150 mg/day).  TMC278 decreased the AUC, Cmax and Cmin of active R-methadone by 16%, 14% and 22%, respectively. Decreases were also seen in the AUC (16%), Cmax (13%) and Cmin (21%) of inactive S-methadone.  Exposure of TMC278 in the presence of methadone was within the expected range. No signs of opiate withdrawal were observed.

Comment

Although no a-priori dose adjustment of methadone is required, clinical monitoring for withdrawal symptoms is recommended as some patients may require dose adjustment.

Ref: Crauwels HM et al. Pharmacokinetic interaction study between TMC278, a next-generation NNRTI and methadone. 11th PK Workshop, 7–9 April 2010, Sorrento, Italy. Abstract 33.

The pharmacokinetic profiles of darunavir and raltegravir were analysed in five HIV/HCV coinfected patients with moderate to severe liver disease. Based on the ultrasonographic and histological evaluation, two patients had HCV-related chronic active hepatitis, and three patients had a diagnosis of cirrhosis (Child Pugh stage B). Trough concentrations were determined 14 and 30 days after starting a raltegravir/darunavir containing regimen.

Mean raltegravir and darunavir trough concentrations in the hepatic impairment group was 637 (mean Ctrough in control group: 221±217 ng/ml) and 8519 ng/mL (mean Ctrough in control group: 3236±2183 ng/ml), respectively. In a sub-group analysis, patients with cirrhosis had higher mean raltegravir Ctrough than patients with active non cirrhotic hepatitis (665 vs 581 ng/mL). The mean darunavir Ctrough was consistently higher in cirrhotic than non cirrhotic patients (9820 vs 2016 ng/mL).

Comment

The data suggest special caution in the use of raltegravir, and especially of darunavir, in patients with moderate to severe liver impairment because of the risk of additionally increased toxicity.

Ref: Tommasi C et al. Raltegravir and darunavir plasma pharmacokinetic in HIV-1 infected patients with advanced liver disease.11th PK Workshop, 7–9 April, 2010, Sorrento, Italy. Abstract 10.

The efavirenz trough concentrations in 17 HIV+ subjects with substance related disorders (SRDs) and 20 HIV-positive subjects without SRDs were evaluated. The median efavirenz trough concentrations in the SRD groups were lower with tobacco (1.76 vs 2.295 ug/ml), alcohol (1.41 vs 2.25 ug/ml), marijuana (1.73 vs 2.24 ug/ml) and cocaine (1.92 vs 2.05mg/ml), but higher with opioids (2.41 vs 1.85 mg/ml). Only the differences with tobacco and alcohol were statistically significant. There was no significant relationship between SRD and antiviral response.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

Atazanavir trough concentrations were evaluated in 32 HIV-positive subjects with substance-related disorders (SRDs) and 35 HIV-positive subjects without SRDs.

The median atazanavir concentrations in the SRD groups were lower with tobacco (0.314 vs 0.712 ug/ml), marijuana (0.238 vs 0.593 ug/ml), alcohol (0.534 vs 0.558 ug/ml), and opioids (0.325 vs 0.712 ug/ml), but higher with cocaine (0.768 vs 0.544 ug/ml).

Trough concentrations in the SRD group were below the therapeutic range in 36% of tobacco users and 50% of marijuana users. Only the differences with tobacco and marijuana were statistically significant. There was no significant direct effect of SRD on viral load or CD4 count.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The effect of darunavir/r (600/100mg twice daily for seven days) on the pharnacokinetics of buprenorphine was assessed in 17 HIV-negative subjects stable on buprenorphine/naloxone maintenance therapy (daily doses up to 24/6mg). There was no effect on buprenorphine AUC, Cmax or trough concentrations; however, norbuprenorphine Cmax increased by 36% and AUC increased by 46%.

No subject required dose adjustment of buprenorphine/naloxone.

Given the increase in norbuprenorphine concentrations, close clinical monitoring of patients is recommended.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The effect of raltegravir (400mg twice daily) on the pharnacokinetics of methadone were investigated in 12 HIV-negative subjects stable on methadone.

There was no change in either methadone AUC or Cmax in the presence of raltegravir and no dose adjustment is required.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The interaction between buprenorphine and didanosine, lamivudine and tenofovir was investigated in 27 HIV-negative buprenorphine/naloxone maintained subjects.

Data for didanosine and tenofovir were compared to values obtained from 20 control subjects not receiving buprenorphine; lamivudine was compared to control data.

No significant changes in buprenorphine pharmacokinetics were observed when coadministered with didanosine, lamivudine and tenofovir. When compared to controls, buprenorphine had no statistically significant effect on NRTI concentrations.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

This study looked at a group of 275 patients, 47% of whom were active users of at least one substance (heroin 2%; cocaine 7%; marijuana 13%; tobacco 43%; alcohol 22%; prescription opioids 14%). It was found that a significantly higher proportion of substance users had antiretroviral trough concentrations below the therapeutic range (23% vs 9%, p=0.048). The proportion of patients with an unfavourable treatment outcome (HIV RNA >75 copies/ml) was significantly higher in the substance user group than in the non-user group (40% vs 28%, p=0.044). However, when adjusted for race, substance abuse was no longer associated with virological response.

References:

Ma Q, et al. Comparison of ART pharmacokinetics and clinical monitoring parameters in HIV-infected patients with and without substance abuse. 16th CROI, Montreal, 2009. Abstract 698.

http://www.retroconference.org/2009/Abstracts/35802.htm

Paper 1 provides clear evidence (data in healthy volunteers) that the effect of ritonavir on methadone clearance results from increased renal clearance and induced hepatic metabolism. It is important to note that the induction of methadone metabolism occurred despite profound CYP inhibition in both intestine and liver (the expected effect). So these data clearly suggest that there is no role for CYP3A4 in methadone metabolism.

Paper 2 describes short term (2 day) and steady-state (2 week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with iv and oral alfentanyl) and P-gp (probed with fexofenadine), and on methadone pharmacokinetics in healthy volunteers. The authors conclude that acute ritonavir inhibits hepatic CYP3A (>70%) and first pass CYP3A (>90%). The fexofenadine data suggested P-gp inhibition. While mild induction of P-gp and hepatic CYP3A by steady state ritonavir was apparent, the overall net effect was still marked inhibition.

References

1. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. _Kharasch E, Bedynek P, Park S, et al. _Clin Pharmacol Ther, 2008, 84(4): 497-505.
http://www.ncbi.nlm.nih.gov/pubmed/18615008
2. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities._Kharasch E, Bedynek P, Walker A, et al. Clin Pharmacol Ther, 2008, 84(4): 506-512.
http://www.ncbi.nlm.nih.gov/pubmed/18615009
Source: www.hiv-druginteractions.org (3 October 2008).
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=398

This was a multiple dose, open-label, sequential, non-randomised study in HIV negative subjects stabilised on at least 3 weeks of BUP/NAL therapy.

At day 7 of concomitant administration, buprenorphine AUC and C24h were not affected by co-administered TPV/r (<6% change relative to BUP/NAL alone) while Cmax decreased approximately 14%. However, although AUC, Cmax and C24h of norbuprenorphine, the major BUP metabolite, were decreased almost 80% and naloxone AUC and Cmax were decreased approximately 44% and 36%, respectively, when coadministered with TPV/r, there was no clinical evidence of opioid withdrawal and no need to modify buprenorphine dose.

Compared to historical controls AUC and C12h tipranavir levels decreased by 26% and 39%, respectively and Cmax was unchanged. Ritonavir C12h was similar, but Cmax and AUC were lower in by 40-50% and 35%, respectively.

The authors concluded that no modification of BUP/NAL is required but that caution should be used when combining BUP/NAL with tipranavir/r due to sgnificantly decreased tipranavir plasma concentrations.

Ref:
Bruce R et al. Pharmacokinetic Interactions between Buprenorphine/Naloxone & Tipranavir/Ritonavir in HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone. 48th ICAAC. Poster abstract A-967a.

Introduction

HIV/AIDS and opioid dependence adversely impact millions of people throughout the world. Explosions in both epidemics are described worldwide and there is no evidence of slowing. As a result, HIV-infected opioid dependent prescribed either methadone or buprenorphine for the treatment of their opioid dependence, may find themselves prescribed antiretrovirals (ARVs) that may result in an adverse interaction. Awareness that pharmacokinetic interactions exist may deter some patients and physicians from initiating potentially life-saving therapy, or lead to adverse consequences among patients already receiving treatment. The reader is pointed to recent reviews that provided greater details regarding interactions between ARVs, treatments for opioid dependence, and drugs of abuse/dependence. [1, 2]

Following is a summary of the key interactions and their management.

Methadone

Methadone, a full opioid agonist, is used for the treatment of pain and opioid dependence. Multiple cytochrome P450 isoenzymes are involved in the metabolism of methadone. [3-6]

The currently approved nucleoside reverse transcriptase inhibitors (NRTIs) do not affect methadone levels in a clinically significant manner and do not precipitate opioid withdrawal and do not result in opioid excess. However, methadone affects the pharmacokinetics of several of the NRTIs. Specifically, several studies have demonstrated that methadone increases zidovudine (ZDV) by approximately 40%. [7-10]

This increase may result in side effects, such as headache, abdominal pain, myalgias, and fatigue, which can all mimic opioid withdrawal. In addition, laboratory abnormalities, such as anemia and hepatitis, may occur due to increased ZDV levels. Results from studies with stavudine (d4T) and didanosine (ddI) have been performed in a between-subject crossover design. [11]

While neither ddI nor d4T affected methadone levels, methadone appeared to alter the dispo­sition of both NRTIs. Although methadone’s decrease in drug levels for d4T was statistically significant, these values are unlikely to be clinically significant. However, methadone’s 66% decrease in the maximum concentration of buffered ddI tablets is clinically significant; the enteric-coated (EC) formulation has corrected this problem and is the preferred formulation when methadone and ddI are co-administered. [12]

In addition to NRTIs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine [13-16] and efavirenz [17-19] are well described in the literature as resulting in the induction of methadone metabolism with resultant opioid withdrawal, often requiring elevations in methadone dosages. Patients taking methaodone who are started on nevirapine or efavirenz should be monitored for signs of opioid withdrawal.

With the exception of tipranavir, the currently available protease inhibitors (PIs) appear to lack significant interactions with methadone. Tipranavir’s package insert states that co-administration of tipranavir boosted with ritonavir and methadone could result in a 50% decrease in the methadone concentration which may require increases in methadone in some patients. [20]

However, the applicability of this study for patients on chronic methadone maintenance is unclear as this study was conducted in opioid-naïve healthy volunteers after a single dose of methadone. [2]

Studies examining other FDA approved classes, namely CCR5 antagonist, maraviroc and integrase inhibitor, raltegravir have not been performed to date.

Buprenorphine

Buprenorphine (BUP) is a partial opioid agonist used for the treatment of opioid dependence. BUP undergoes N-dealkylation to norbuprenorphine by cytochrome P450 isoenzyme 3A4 and these metabolites are glucuronidated by UGT1A1. [21. 22. 23]

Two recent reviews have delineated all the ARVs studied to-date with buprenorphine. [1, 2]

In summary, compounds that lower buprenorphine levels appear not to affect the pharmacodynamic properties of buprenorphine. This was demonstrated in efavirenz’s ability to lower buprenorphine concentrations without precipitating withdrawal. [24]

In addition, compounds that elevate buprenorphine levels, such as ritonavir and delavirdine, appear not to alter buprenorphine’s pharmacodynamic profile as they did not produce opioid excess. [25]

The one exception to this seeming lack of pharmacodynamic interactions with ARVs may be in the case of atazanavir, which shares the UGT 1A1 pathway with BUP. [26. 27]

Although surveillance for opioid excess is encouraged in the co-administration of atazanavir and buprenorphine, the two can be safely administered with appropriate observation.

Studies examining other FDA approved classes, namely CCR5 antagonist, maraviroc, and integrase inhibitor, raltegravir have not been performed to date.

Management of interaction-induced opiod withdrawal or excess

The time course of symptom development due to medication interactions is highly variable. Typically, inhibition of cytochrome P450 enzymes can occur as soon as an inhibiting medication is started, with associated symptoms (typically of opioid excess) appearing shortly thereafter. Induction of P450 isoenzymes occurs more slowly, however, typically taking 10 to 21 days; however, these are general timeframes. When alternative explanations for apparent symptoms of opioid withdrawal or excess have been considered but discounted (e.g., thy­roid dysfunction, new onset of cocaine use, etc.), an empiric change in methadone dose may be indicated with careful follow-up.

Clinicians should not be reluctant to suggest opioid pharmacotherapy dose changes in the absence of definitive data regarding a specific interaction since substantial between subject variation exists. In addition, not all interactions between opioid agonist treatments and single antiretrovirals, let alone typical multi-medication regimens, have been studied. In everyday practice, with patients taking multiple medications for multiple comorbidities, the risk for interactions is significantly greater.

In the United States, patients receiving methadone treatment for opioid dependence are enrolled in licensed methadone maintenance treatment programs (MMTPs). The physician at the MMTP is responsible for prescribing the patient’s methadone. Co-ordination of care between MMTP and HIV care settings is critical.

A common scenario consists of an HIV specialist prescribing antiretroviral therapy to a patient receiving methadone in an MMTP. A phone conversation between the HIV physician and the MMTP physician can be enormously helpful to the patient’s care when a medication interaction is anticipated or suspected. Therefore, when a new antiretroviral known to significantly interact with methadone is started (e.g., efavirenz or nevirapine) in methadone maintained patients, the HIV clinician should contact the prescribing physician at the MMTP immediately to coordinate care. This pre-emptive intervention will allow the MMTP to be alert to the need for a methadone dose increases if withdrawal symptoms are precipitated.

Although exact schedule of increase has not been comprehensively studied, the following guidelines are in agreement with expert opinion. Importantly, dosing may vary from patient-to-patient, as not all patients will develop opiate withdrawal. A reasonable plan is to routinely screen all patients for opiate withdrawal beginning on the fourth day of starting the new antiretroviral medication. Additionally, patients should be alerted to the possibility of precipitated withdrawal so they can notify staff should symptoms develop. If symptoms develop, the methadone dose should be immediately increased by 10 mg every 2-3 days until symptoms abate. Coordinating care between HIV treatment clinician and the MMTP physician can thus minimise the potential negative impact of opiate withdrawal symptoms as a stimulus for non-adherence to antiretroviral therapy or relapse to illicit opioid use. If the inciting antiretroviral is discontinued, the methadone dose should be gradually reduced to pre-treatment levels over the course of one to two weeks.

If available, a serum methadone trough level can inform situations where an interaction may be suspected. If low, this information may assist in reassuring the patient, or the program, that a methadone dose increase is indeed indicated.

However, if a patient is taking zidovudine (ZDV) and methadone and complains of opioid withdrawal, reduction in ZDV dose should be considered first. If drowsiness or other symptoms of methadone excess are reported, a reduction in methadone dose should be considered. A high serum methadone trough level would further support the clinical findings.

In the US, buprenorphine can be prescribed by any physician who has received a waiver from the DEA. The evaluation and treatment of BUP and ARV interactions, therefore, will be managed primarily by HIV practitioners. Due to the long half-life and high binding affinity of BUP, and the initial data presented above, it is anticipated that buprenorphine may have fewer medication interactions with antiretroviral medications than methadone.

Risk reduction

Opioid dependence is a relapsing medical disorder and HIV clinicians should understand that patients on methadone or buprenorphine may relapse into illicit use of substances. The relapsing nature of opioid dependence and the wide array of serious infectious and other medical consequences due to relapse, requires the development of preventive risk reduction strategies. Risk reduction is based on the underlying principle that opioid dependence is a chronic and relapsing disease which may not be cured in the individual or eliminated from society but can be conducted in a way that minimises harm to the user and others.

While complete cessation of drug use remains a laudable goal, reduction in drug use frequency and safer injection practices is more realistic for many drug users until abstinence can be achieved. Risk reduction strategies have been effectively incorporated into some drug treatment programs, syringe exchange programs and safe injection rooms. [28, 29]

There are several practical components inherent to risk reduction strategies. Education about and provision of drug use paraphernalia (e.g., needles and syringes) for more hygienic injection practices for the prevention of infectious complications of injection are essential. In addition to the distribution or exchange of injection equipment, these programs typically include HIVAIDS education, condom distribution, and referral or enrollment in a variety of drug treatment, medical, and social services. [30]

The ultimate goal of risk-reduction strategies should be the reduction or prevention of illicit drug use itself, the development of strategies that will minimise the serious medical consequences of drug misuse, and the development of strategies that will eliminate drug misuse and its root causes. Until we are successful in this arena, we stand little chance of limiting the spread and consequences of HIV disease in this and related populations.

References

1. Bruce RD, McCance-Katz, E, Karasch E.D., Moody, D.E., Morse G.D. Pharmacokinetic Interactions Between Buprenorphine and Antiretroviral Medications. Clinical Infectious Diseases 2006,43:S216-223.
2. Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. Journal of Acquired Immune Deficiency Syndromes: JAIDS 2006,41:563-572.
3. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metabolism & Disposition 2003,31:742-747.
4. Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, et al. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. Journal of Clinical Psychopharmacology 2002,22:211-215.
5. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chemical Research in Toxicology 1996,9:365-373.
6. Wu D, Otton SV, Sproule BA, Busto U, Inaba T, Kalow W, Sellers EM. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. British Journal of Clinical Pharmacology 1993,35:30-34.
7. McCance-Katz EF, Rainey PM, Friedland G, Kosten TR, Jatlow P. Effect of opioid dependence pharmacotherapies on zidovudine disposition. American Journal on Addictions 2001,10:296-307.
8. McCance-Katz EF, Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology 1998,18:435-443.
9. Rainey PM, Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews L, et al. The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects. American Journal on Addictions 2002,11:66-74.
10. Schwartz EL, Brechbuhl AB, Kahl P, Miller MA, Selwyn PA, Friedland GH. Pharmacokinetic interactions of zidovudine and methadone in intravenous drug-using patients with HIV infection. Journal of Acquired Immune Deficiency Syndromes 1992,5:619-626.
11. Rainey PM, Friedland G, McCance-Katz EF, Andrews L, Mitchell SM, Charles C, Jatlow P. Interaction of methadone with didanosine and stavudine. Journal of Acquired Immune Deficiency Syndromes: JAIDS 2000,24:241-248.
12. Friedland G, Rainey P, Jatlow P, Andrews L, Damle B, McCance-Katz EF. Pharmacokinetics (PK) of didanosine (ddI) from encapsulated enteric coated bead formulation (EC) vs chewable tablet formulation in patients (pts) on chronic methadone therapy. In: 14th International AIDS Conference. Barcelona, Spain: International AIDS Society; 2002.
13. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999,13:957-962.
14. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clinical Infectious Diseases 2001,33:1595-1597.
15. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy 1999,19:471-472.
16. Stocker H, Kruse G, Kreckel P, Herzmann C, Arasteh K, Claus J, et al. Nevirapine significantly reduces the levels of racemic methadone and (R)-methadone in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004,48:4148-4153.
17. Marzolini C, Troillet N, Telenti A, Baumann P, Decosterd LA, Eap CB. Efavirenz decreases methadone blood concentrations. AIDS 2000,14:1291-1292.
18. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. British Journal of Clinical Pharmacology 2001,51:213-217.
19. Pinzani V, Faucherre V, Peyriere H, Blayac JP. Methadone withdrawal symptoms with nevirapine and efavirenz.[see comment]. Annals of Pharmacotherapy 2000,34:405-407.
20. Product Information: Aptivus (r), tipranavir. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2005.
21. Cone EJ, Gorodetzky CW, Yousefnejad D, Buchwald WF, Johnson RE. The metabolism and excretion of buprenorphine in humans. Drug Metabolism & Disposition 1984,12:577-581.
22. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos 2005,33:689-695.
23. King CD, Green MD, Rios GR, Coffman BL, Owens IS, Bishop WP, Tephly TR. The glucuronidation of exogenous and endogenous compounds by stably expressed rat and human UDP-glucuronosyltransferase 1.1. Arch Biochem Biophys 1996,332:92-100.
24. Mcance-Katz E, Moody, DE, Morse, GD, Pade, P, Baker, J, Alvanzo, A, Smith, P, Ogundele, A, Jatlow, P, Rainey, PM. Interactions between Buprenorphine and Antiretrovirals. I. The Nonnucleoside Reverse-Transcriptase Inhibitors Efavirenz and Delavirdine. Clinical Infectious Diseases 2006,43:S224-S234.
25. McCance-Katz EF, Moody DE, Smith PF, Morse GD, Friedland G, Pade P, et al. Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir. Clin Infect Dis 2006,43 Suppl 4:S235-246.
26. Bruce RD, Altice FL. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS 2006,20:783-784.
27. MCCance-Katz E, Pade, P, Morse, GD, Moody, DE, Rainey, PM. . Interaction between buprenorphine and atazanavir. In: College on Problems of Drug Dependence. Scottsdale, AZ; 2006.
28. Broadhead R, Altice, FL. Safer injection facilities in North America: Their place in public policy and health initiatives. J Drug Issues 2002,32:329-356.
29. Broadhead R, Borch, C, van Hulst, Y, Ferrell, J, Villemez, W, Altice, FL. Safer Injection Sites in New York Ciety: A Utilization Survey of Injection Drug Users. J Drug Issues 2003,33:533-538.
30. Compendium of HIV prevention interventions with evidence of effectiveness.: Centers for Disease Control ^& Prevention. National Center for HIV, STD and TB Prevention; 2001.