Share this article on:

The Pharmacokinetic and Pharmacodynamic Interactions Between Buprenorphine/Naloxone and Elvitegravir/Cobicistat in Subjects Receiving Chronic Buprenorphine/Naloxone Treatment

Bruce, Robert Douglas MD, MA, MSc*; Winkle, Peter MD; Custodio, Joseph M. PhD; Wei, Lilian Xuelian PhD; Rhee, Martin S. MD; Kearney, Brian P. PhD; Ramanathan, Srinivasan PhD; Friedland, Gerald H. MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1st, 2013 - Volume 63 - Issue 4 - p 480–484
doi: 10.1097/QAI.0b013e3182961d31
Clinical Science

Background: Interactions between HIV and opioid-dependence therapies are known to occur. We sought to determine if such interactions occurred between buprenorphine/naloxone and elvitegravir boosted with cobicistat.

Methods: We performed a within-subject open-labeled pharmacokinetic and pharmacodynamic study in 17 HIV-seronegative subjects stabilized on at least 2 weeks of buprenorphine/naloxone therapy. Subjects underwent baseline and steady state evaluation of the effect of elvitegravir 150 mg once daily boosted with 150 mg once daily of cobicistat (EVG/COBI) on buprenorphine/naloxone parameters. Safety was monitored throughout the study.

Results: Compared with baseline values, buprenorphine mean AUCtau (69.0 versus 95.6 hr*ng/mL) and mean Cmax (8.4 versus 9.3 ng/mL) increased significantly in the presence of EVG/COBI. Compared with baseline values, norbuprenorphine mean AUCtau (103.4 versus 163.4 hr*ng/mL) and mean Cmax (6.9 versus 9 ng/mL) also increased significantly after achieving steady state EVG/COBI. Naloxone mean AUCtau (0.57 versus 0.45 hr*ng/mL) and mean Cmax (0.25 versus 0.16 ng/mL) decreased after the addition of EVG/COBI. The AUCtau, Cmax and Ctau of EVG and cobicistat did not significantly differ from historical controls. Opioid withdrawal or overdose was not observed among subjects in this study.

Conclusion: The addition of EVG/COBI to stabilized patients receiving buprenorphine/naloxone modestly increased buprenorphine and norbuprenorphine levels without affecting the opioid pharmacodynamics.

*Yale University AIDS Program, New Haven, CT;

Anaheim Clinical Trials, Anaheim, CA; and

Gilead Sciences, Inc, Foster City, CA.

Correspondence to: R. Douglas Bruce, MD, MA, MSc, Yale University AIDS Program, 135 College Street, Suite 323, New Haven, CT 06510 (e-mail:

Supported by Gilead Sciences, Inc, and the National Institutes of Health Grant R01DA025932. Gilead is the maker of elvitegravir and cobicistat, which are investigated in this study.

Received January 23, 2013

Accepted April 01, 2013

Back to Top | Article Outline


Substantial advances in the treatment of opioid dependence have been made in recent years. These have had a favorable impact on clinical and public health outcomes of patients with both opioid dependence and HIV/AIDS.1 Medication-assisted treatment with methadone or buprenorphine (BUP) improves adherence to antiretroviral therapy2 and is effective for both primary and secondary HIV prevention.3,4 BUP, unlike methadone, can be prescribed by any physician in primary care who has completed 8 hours of required training and obtained a waiver to prescribe. BUP, a partial mu-receptor agonist, is most commonly prescribed in its coformulation with naloxone (NLX) to reduce diversion. This potentially allows for the expansion of drug treatment and integration of substance abuse treatment into HIV and other clinical care settings.5,6

The number of people eligible for and receiving treatments for both opioid dependence and HIV infection has increased. Coadministration of these therapies, however, has been associated with both pharmacokinetic (PK) and pharmacodynamic interactions, with important clinical consequences.7–11 The concern about such interactions may deter some patients or providers from initiating potentially life-saving therapy.12 Such interactions may lead to nonadherence with antiretroviral regimens, development of viral resistance, and lack of efficacy of HIV therapy.2,8 Opioid-dependent patients may also experience adverse effects from HIV treatment that mimic opioid withdrawal and may relapse to using opioids13 or other illicit substances (eg, cocaine and alcohol) to alleviate symptoms. The occurrence of unrecognized drug interactions may therefore lead to a lack of success of treatment for HIV, opioid dependence, or both.14

BUP is extensively metabolized via the N-dealkylation of its N-cyclopropylmethyl group to norbuprenorphine (norBUP) via CYP3A4, 3A5, 3A7, and 2C8, whereas norBUP is further metabolized by CYP3A4.15,16 NorBUP is an active metabolite of BUP but possesses 2% of the analgesic potency of BUP.17 The glucuronidation of BUP is performed by UGT1A1, 1A3, 2B7, and 2B17, whereas glucuronidation of norBUP is performed by UGT1A1 and 1A3.18,19 BUP and metabolites are mainly excreted into the bile where they may undergo enterohepatic circulation.15

Elvitegravir (EVG) is an HIV-1 integrase inhibitor that is metabolized by CYP3A.20 Cobicistat (COBI) is a new pharmacoenhancer that is a structural analog of ritonavir and is a potent mechanism-based inhibitor of CYP3A with greater specificity than ritonavir and without anti-HIV activity.21 In addition, it is a weak inhibitor of CYP2D6; however, it is not an inhibitor of UGT. To reduce the frequency of EVG dosing, COBI was developed to facilitate once daily coadministration and is currently coformulated with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) into the EVG/COBI/FTC/TDF single-tablet regimen indicated for treatment of HIV-1 infection in adults who are antiretroviral treatment naive. Coformulations with other antiretroviral treatments (eg, atazanavir and darunavir) and COBI are currently underway.

Simplified HIV regimens are preferred for HIV-infected opioid-dependent patients to improve adherence, and the EVG/COBI/TDF/FTC coformulation may be a useful medication in the armamentarium of the HIV clinical provider caring for the HIV-infected opioid-dependent patient. This study was undertaken to examine possible interactions between BUP/NLX and EVG/COBI, given the high probability of clinical administration of both medications in clinical practice.

Back to Top | Article Outline


Study Design

This was a multiple dose, open-label, sequential, nonrandomized study in BUP-maintained HIV-negative subjects stabilized on at least 2 weeks of BUP/NLX therapy. Subjects were eligible if they were (1) HIV-seronegative; (2) aged ≥ 18 and ≤60 years; (3) with a body mass index 19 to 34 kg/m2; (4) not being treated with concomitant medications that might alter drug disposition; (5) without clinically significant medical conditions as determined by medical history, physical examination, electrocardiogram, complete blood count, hepatic transaminases, and creatinine and were not pregnant. Urine toxicology for amphetamines, benzodiazepines, cocaine, marijuana, opiates, and oxycodone was performed at baseline and repeated before conducting drug disposition studies. Subjects who screened positive for any of these substances in the urine toxicology were excluded from further evaluation.

Except for EVG/COBI pharmacokinetics, subjects served as their own controls. At baseline, subjects on steady state BUP/NLX were hospitalized and underwent PK investigation over a 24-hour inpatient period. Blood specimens were drawn predose and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours after dosing. All subjects were on a stable dose of BUP/NLX between 16/4 and 24/6 mg once daily.

Subsequently, EVG 150 mg plus COBI 150 mg were administered once daily with food for 10 days under direct observation to insure adherence and to monitor for adverse events. After achieving EVG steady state, serial blood samples were collected from each subject over a 24-hour inpatient period to determine the plasma drug concentration-time profile of EVG, COBI, BUP, norBUP, and NLX. Blood specimens were drawn predose and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 24 hours after dosing. During the inpatient hospitalization period, all the subjects had standardized meals administered at the same time relative to medication dosing to minimize any effect of food relative to the PK parameters.

Study procedures included standardized measures of opioid withdrawal and opioid excess using the objective opioid withdrawal scale (OOWS), subjective opioid withdrawal scale (SOWS),22 the clinical opioid withdrawal scale (COWS), and the opioid overdose assessment scale (OOAS).23 These scales were administered on a daily basis by trained nursing staff before the morning dose administration of BUP/NLX and EVG/COBI. Adverse symptoms were recorded in a standardized manner. This study was approved by institutional review board.

Back to Top | Article Outline

Bioanalytical Procedures

Concentrations of EVG, COBI, BUP, norBUP, and NLX in plasma samples were determined using fully validated high-performance liquid chromatography–tandem mass spectroscopy bioanalytical methods at QPS, Inc (Newark, DE). Sample analyses for EVG were performed as follows: 50 µL of human plasma was spiked with deuterated internal standard and processed by solid phase extraction. The lower limit of quantitation for EVG was 20 ng/mL. The interassay precision range (%CV) for EVG was 2.8 to 8.1. COBI was analyzed in 50 µL of human plasma spiked with a deuterated internal standard and then extracted using protein precipitation with methanol. The lower limit of quantitation for COBI was 5 ng/mL. The interassay precision range (%CV) for COBI was 3.9 to 8.3.

Sample analyses for BUP were performed as follows: 500 µL of human plasma was spiked with a deuterated internal standard followed by liquid–liquid extraction with methanol. The lower limit of quantitation for BUP was 20 ng/mL. The interassay precision range (%CV) for BUP was 3.8 to 7.2. NorBUP was analyzed in 500 µL of human plasma spiked with a deuterated internal standard and then extracted using protein precipitation with methanol. The lower limit of quantitation for norBUP was 20 ng/mL. The interassay precision range (%CV) for norBUP was 5.2 to 9.0. NLX was analyzed in 250 µL of human plasma was spiked with a deuterated internal standard followed by liquid–liquid extraction with methanol. The lower limit of quantitation for NLX was 20 ng/mL. The interassay precision range (%CV) for NLX was 15.7 at the lower limit of quantitation and 4.0 to 7.2 above the lower limit of quantitation.

Back to Top | Article Outline

PK and Statistical Analysis

Plasma concentration and PK parameters were summarized using descriptive statistics for each analyte by treatment (ie, BUP/NLX plus EVG/COBI versus BUP/NLX alone). Natural logarithm transformation of concentrations and selected PK parameters for each analyte (ie, BUP, norBUP, NLX, COBI, and EVG) were applied for PK analysis. The following PK parameters were determined: AUCtau is the area under the concentration versus time curve over the dosing interval; Cmax is the maximum observed concentration of drug in plasma; Cmin is the minimum observed concentration of drug in plasma; Ctau is the observed drug concentration at the end of the dosing interval; Clast is the last observed quantifiable concentration of drug in plasma. A parametric (normal theory) analysis of variance using a mixed-effects model was fitted to the natural logarithmic transformation of PK parameters (AUCtau, Cmax, and Ctau) of BUP, norBUP, and NLX. The 90% confidence intervals were constructed for the ratio of geometric means of each of the PK parameters (AUCtau, Cmax, and Ctau) of BUP, norBUP, and NLX between BUP/NLX plus EVG/COBI (test treatment) and BUP/NLX alone (reference treatment). Equivalence of exposures was evaluated using boundaries of 70%–143%, which were used to test whether there was at least a 30% difference in each PK parameter when BUP/NLX is coadministered with EVG/COBI at steady state versus when BUP/NLX is administered alone. This 30% difference was chosen because a change of this magnitude is likely to be necessary to experience opioid withdrawal or excess. The PK of EVG and COBI were compared with historical data when given as EVG/COBI in healthy volunteers.24 A formal statistical analysis was not used in comparing the EVG/COBI in this study to the historical data, as the EVG/COBI plasma concentrations in this study are consistent with the substantial body of data now available for EVG/COBI.

Back to Top | Article Outline


Study Disposition

Eighteen individuals (15 men and 3 women; 16 white, 1 black, and 1 not specified; 4 Hispanic and 14 non-Hispanic) consented to the study and 1 withdrew consent before taking any study drug and was therefore excluded form this analysis. Median (min–max) age, height, weight, and body mass index were 38 (25–57) years, 174.0 (151.1–185.4) cm, 82.3 (61.6–104.3) kg, and 27.6 (20.8–33.3) kg/m2, respectively. None of the subjects developed adverse events requiring study discontinuation, although 1 did develop a serious and grade 3 ulnar nerve injury postphlebotomy that was unrelated to study drug.

Back to Top | Article Outline

PK Outcomes

PK outcome data for BUP is summarized in Table 1 and graphically represented in Figure 1. The mean AUCtau of BUP increased 35% after the coadministration with EVG/COBI from 69.0 versus 95.6 hr*ng/mL, respectively, with a geometric least squares (GLS) mean ratio of 135.26 with 90% CI (118.25 to 154.72). The Cmax of BUP, however, did not differ statistically before and after the administration of EVG/COBI (8.4 versus 9.3 ng/mL; GLS mean ratio of 111.69 with 90% CI: 97.94 to 127.36). The Ctau of BUP significantly increased by 66% after the coadministration with EVG/COBI (1.4 to 2.4 ng/mL; GLS mean ratio 166.28 with 90% CI: 143.14 to 193.17).





PK data for norBUP is also summarized in Table 1 and graphically represented in Figure 2. Compared with baseline values, the AUCtau of norBUP increased 42% after coadministration with EVG/COBI (103.4 versus 163.4 hr*ng/mL; GLS mean ratio 142.45 with 90% CI: 121.60 to 166.88). The Cmax of norBUP increased 24% after coadministration with EVG/COBI (6.9 versus 9.0 ng/mL; GLS mean ratio 123.71 with 90% CI: 102.67 to 149.05). The Cmin of norBUP increased by 57% after coadministration with EVG/COBI (3.6 versus 6.4 ng/mL; GLS mean ratio 156.89 with 90% CI: 130.66 to 188.39).



PK data for NLX is summarized in Table 1 and graphically represented in Figure 3. The AUCtau of NLX before and after the coadministration with EVG/COBI revealed a 28% reduction in NLX levels (0.568 versus 0.449 hr*ng/mL, respectively; GLS mean ratio of 71.57 with 90% CI: 58.65 to 87.33]). The Cmax of NLX was also reduced after the coadministration with EVG/COBI (0.249 to 0.164 ng/mL, respectively; GLS mean ratio 72.13 with 90% CI: 61.44 to 84.67). The Ctau was below the limit of quantitation for all subjects for both treatments.



The AUCtau, Cmax, and Ctau of EVG did not differ from historical controls: 16,979.9 versus 18,695.8 hr*ng/mL; 1,530.9 versus 2,150.6 ng/mL; and 324 ng/mL versus 318 ng/mL, respectively. The AUCtau, Cmax, and Ctau of COBI did not differ from historical controls: 8,593.0 versus 10,389.4 hr*ng/mL; 1,204.2 versus 1,399.7 ng/mL, and 39.7 versus 32.3 ng/mL, respectively.24

Back to Top | Article Outline

Clinical Outcomes

The OOWS, SOWS, COWS, and the OOAS were used to monitor the clinical effects of coadministration of BUP/NLX with EVG/COBI. These instruments were used before and throughout coadministration with EVG/COBI. No significant signs of withdrawal or excess occurred during the course of this study and no dosage adjustments for BUP were required. Composite scores for each validated instrument are listed below with its respective standard deviation: OOWS scores 0.2 ± 0.39 (maximum 13); SOWS, 1.6 ± 2.29 (maximum 64); COWS, 0.5 ± 0.94 (maximum 48); and OOAS, 0.4 ± 0.80 (maximum 40).

Back to Top | Article Outline


In this PK study examining steady state BUP/NLX in HIV-seronegative subjects, coadministration of EVG/COBI significantly increased the AUC of BUP by 35% and norBUP by 42%. Despite these increases in plasma concentrations, no evidence of opioid excess or withdrawal was observed. This increase in BUP plasma concentrations is consistent with COBI inhibition of BUP metabolism at CYP3A4. The increase in norBUP is interesting because the glucuronidation of norBUP occurs primarily through UGT1A1 and 1A3, which are not inhibited by COBI.18

Interestingly, NLX levels decreased with the administration of EVG/COBI. NLX is metabolized by both UGTs (specificity unknown) and CYPs, the latter recently identified as CYP2C18 and 2C19.25 The etiology of the reduction in NLX plasma levels is unknown and further research is needed to ascertain the mechanisms involved in these pharmacological differences. Interestingly, a reduction in NLX was also seen in a PK study with tipranavir boosted with ritonavir.11 Because NLX is an opioid antagonist included in the coformulated tablet for the purpose of reducing diversion in the setting of BUP/NLX injection, a reduction in plasma concentration of NLX will not compromise the efficacy of BUP in the treatment of opioid dependence.

Despite these PK interactions, the 3 validated scales administered to subjects daily confirmed the lack of a clinical effect associated with these PK changes. Moreover, this was clinically confirmed by the absence of a need to adjust BUP/NLX dosing in all subjects and no discontinuations from the study because of symptoms of opioid withdrawal.

It is a common practice in the treatment of HIV in this population to seek HIV regimens with a minimum pill burden as pill burden is inversely correlated with adherence in this population.26 The once daily fixed dose combination of EVG/COBI/TDF/FTC is likely to be a popular choice of HIV therapy in this population. Because BUP/NLX can also be prescribed in primary care settings by appropriate licensed physicians, it is likely that HIV-infected opioid-dependent patients will receive both BUP/NLX and EVG/COBI. The lack of a clinical effect of EVG/COBI on BUP/NLX seen in this study is therefore of clear clinical importance. The ability to access BUP/NLX from the same HIV clinical provider is a clear advantage allowing patients with both disorders to receive effective medications to improve health outcomes.4,6

The results from this study are subject to several limitations. First, the sample size was small, although within the range of similar drug–drug interaction studies. Second, this study used a within-subject design with patients acting as their own controls (thereby resulting in less intrapatient variability); however, given this study design, it was not possible to directly compare the effect on EVG/COBI parameters before and after BUP administration. This comparison necessitated a less precise between-subject comparison with the use of historical controls. Nevertheless, the results of these comparisons with the study subjects were not significantly different.

Back to Top | Article Outline


The addition of EVG boosted with COBI to stabilized HIV-uninfected patients receiving BUP/NLX increased BUP PK parameters without pharmacodynamic effect. EVG/COBI levels in these subjects did not differ statistically from historical controls. BUP/NLX and EVG/COBI can be safely coadministered without dosage modification.

Back to Top | Article Outline


1. Bruce RD, Altice FL, Friedland GH. HIV Disease among Substance Users: Treatment Issues. In: Volberding P, ed. Global HIV/AIDS Medicine. New York: Elsevier; 2007.
2. Lucas GM, Mullen BA, McCaul ME, et al.. Adherence, drug use, and treatment failure in a methadone-clinic-based program of directly administered antiretroviral therapy. AIDS Patient Care STDS. 2007;21:564–574.
3. Kerr T, Wodak A, Elliott R, et al.. Opioid substitution and HIV/AIDS treatment and prevention. Lancet. 2004;364:1918–1919.
4. Altice FL, Sullivan LE, Smith-Rohrberg D, et al.. The potential role of buprenorphine in the treatment of opioid dependence in HIV-infected individuals and in HIV infection prevention. Clin Infect Dis.2006;43(suppl 4):S178–S183.
5. Basu S, Smith-Rohrberg D, Bruce RD, et al.. Models for integrating buprenorphine therapy into the primary HIV care setting. Clin Infect Dis. 2006;42:716–721.
6. Altice FL, Bruce RD, Lucas GM, et al.. HIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/naloxone treatment within HIV clinical care settings: results from a multisite study. J Acquir Immune Defic Syndr. 2011;56(suppl 1):S22–S32.
7. Bruce RD, Altice FL. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS. 2006;20:783–784.
8. Bruce RD, Altice FL, Gourevitch MN, et al.. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J Acquir Immune Defic Syndr. 2006;41:563–572.
9. Bruce RD, McCance-Katz E, Kharasch ED, et al.. Pharmacokinetic interactions between buprenorphine and antiretroviral medications. Clin Infect Dis. 2006;43(suppl 4):S216–S223.
10. Spire B, Lucas GM, Carrieri MP. Adherence to HIV treatment among IDUs and the role of opioid substitution treatment (OST). Int J Drug Policy. 2007;18:262–270.
11. Bruce RD, Altice FL, Moody DE, et al.. Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone. Drug Alcohol Depend. 2009;105:234–239.
12. Lucas GM, Gebo KA, Chaisson RE, et al.. Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic. AIDS. 2002;16:767–774.
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. Bruce RD, Altice FL. Clinical care of the HIV-infected drug user. Infect Dis Clin North Am. 2007;21:149–179, ix.
15. Cone EJ, Gorodetzky CW, Yousefnejad D, et al.. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos. 1984;12:577–581.
16. Chang Y, Moody DE, McCance-Katz EF. Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos. 2006;34:440–448.
17. Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet. 2005;44:661–680.
18. Chang Y, Moody DE. Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases. Drug Metab Lett. 2009;3:101–107.
19. Rouguieg K, Picard N, Sauvage FL, et al.. Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes. Drug Metab Dispos. 2010;38:40–45.
20. Ramanathan S, Mathias AA, German P, et al.. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011;50:229–244.
21. Mathias AA, German P, Murray BP, et al.. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2010;87:322–329.
22. Handelsman L, Cochrane KJ, Aronson MJ, et al.. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13:293–308.
23. Friedland G, Andrews L, Schreibman T, et al.. Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction. AIDS. 2005;19:1635–1641.
24. Ramanathan S, Wang H, Stondell T, et al.. Pharmacokinetics and drug interaction profile of cobicistat boosted-elvitegravir with atazanavir, rosuvastatin, or rifabutin. Paper Presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012; Barcelona, Spain. Vol O_03.
25. Fang WB, Chang Y, McCance-Katz EF, et al.. Determination of naloxone and nornaloxone (noroxymorphone) by high-performance liquid chromatography-electrospray ionization- tandem mass spectrometry. J Anal Toxicol. 2009;33:409–417.
26. Bruce RD, Kresina TF, McCance-Katz EF. Medication-assisted treatment and HIV/AIDS: aspects in treating HIV-infected drug users. AIDS. 2010;24:331–340.

buprenorphine/naloxone; elvitegravir; cobicistat; pharmacokinetics; substance abuse

© 2013 by Lippincott Williams & Wilkins