Pharmacokinetic drug interactions have the potential to reduce significantly the antiretroviral or drug treatment benefit that patients gain from each therapy, secondary to alterations in either plasma or tissue levels of one or both agents .
In this report, we present the first cases of symptomatic adverse side-effects, temporally associated with the induction and stabilization of buprenorphine in patients administered the combination of atazanavir and ritonavir. Although the patients were also taking nucleoside reverse transcriptase inhibitors, there is no predicted interaction between these compounds on the basis of their currently understood pharmacokinetics (Table 1).
Patient 1 was inducted with buprenorphine and was titrated to a stable dose of 14 mg/day. Two days after induction, the combination of enteric-coated didanosine 250 mg, tenofovir 300 mg, atazanavir 300 mg and ritonavir 100 mg were all started once a day and co-administered with buprenorphine. The following day, the patient began to experience daytime somnolence and decreased mental functioning. Buprenorphine dosing was not decreased initially, but the patient was offered increased counseling for the next 2 weeks. In recognition of a potential drug interaction of buprenorphine with known inhibitors of CYP3A4, the patient's buprenorphine dose was decreased to 8 mg/day, with tolerance to the sedative effects occurring within 7 days.
Patient 2 had for several months received enteric-coated didanosine 250 mg, tenofovir 300 mg, atazanavir 300 mg and ritonavir 100 mg and twice-daily olanzepine 5 mg. On day 2 of induction with buprenorphine (8 mg), the patient reported feeling ‘doped up’. Despite attempts to maintain the patient on 8 mg/day, the buprenorphine dose was reduced to every other day, with an improvement in the feelings of opiate excess.
Patient 3 had for several months received the once-daily combination of lamivudine 300 mg, tenofovir 300 mg and atazanavir 400 mg while incarcerated. After release from prison, atazanavir dosing was adjusted to 300 mg and combined with ritonavir 100 mg in recognition of the interaction between tenofovir and atazanavir. To avoid relapse to heroin use, the patient requested buprenorphine and was initiated at 8 mg a day. The patient described dizziness and feeling ‘high’ and ‘overmedicated’, and requested a dose modification. Buprenorphine dosing was successfully changed to 8 mg every other day. Although the dizziness improved on alternate day dosing, a craving for opiates occurred. Therefore, buprenorphine was increased to 8 mg a day and further increased to 12 mg a day. The patient then developed hypersomnolence similar to patients 1 and 2. Despite the hypersomnolence, the patient elected to continue buprenorphine at this dose because it reduced the craving for opiates. Continued supportive counseling was provided and tolerance developed over the following week with the gradual cessation of hypersomnolence.
This small case series is the first to suggest and document possible clinical drug interactions between buprenorphine and two protease inhibitors known to inhibit CYP3A4. Briefly, the primary route of buprenorphine phase I metabolism is via CYP3A4 to norbuprenorphine [2,3]. The glucuronidation of buprenorphine metabolites is the most significant part of their phase II metabolism .
A small in-vitro study in liver microsomes  demonstrated an increase in buprenorphine levels probably caused by the inhibition of buprenorphine metabolism by ritonavir at CYP3A4. Atazanavir also appeared to inhibit the metabolism of compounds at CYP3A4 . In pharmacokinetic studies, atazanavir has not been demonstrated to increase the levels of methadone or result in symptoms of opiate excess . In clinical trials, however, atazanavir increased saquinavir levels, thus requiring reduced dosing of saquinavir when combined . A recent pharmacokinetic study  demonstrated that both atazanavir and ritonavir independently boosted saquinavir drug levels, possibly through independent mechanisms. Atazanavir is also an inhibitor and inducer of p-glycoprotein  and an inhibitor of uridine diphosphate-glucuronosyl transferase 1A1 . Importantly, uridine diphosphate-glucuronosyl transferase 1A1 is involved in the phase II metabolism of buprenorphine , and its inhibition by atazanavir may further increase drug levels. Therefore, in these three cases, it is possible that atazanavir or ritonavir inhibited the major phase I metabolic pathway (CYP3A4), or that atazanavir inhibited the major phase II pathway for buprenorphine, resulting in increased levels and clinical symptoms of opiate excess. Until further data are available, specifically from well-conducted pharmacokinetic drug interaction studies of buprenorphine with ritonavir, atazanavir or both, the use of buprenorphine in combination with ritonavir and atazanavir should be undertaken cautiously. Induction with buprenorphine should begin at reduced dosing, and dose escalation should occur at a slower than usual pace to allow providers to assess for opiate excess and to allow patients to become accustomed to the effects of buprenorphine.
Sponsorship: The authors would like to thank the National Institute on Drug Abuse (R01-DA 13805, K24-DA 017072) and the Substance Abuse and Mental Health Services Agency (H79 TI 15767) for their funding and continued support in these research and clinical efforts.
1. Piscitelli SC, Flexner C, Minor JR, Polis MA, Masur H. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:685–693.
2. Iribarne C, Picard D, Dreano Y, Bail JP, Berthou F. Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci 1997; 60:1953–1964.
3. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N, Ishizaki T, Kuroiwa Y. Human buprenorphine N-dealkylation is catalyzed by cytochrome P4503A4. Drug Metab Dispos 1998; 26:818–821.
4. Chang Y, Moody DE, McCance-Katz EF. Novel metabolites of buprenorphine detected in human liver microsomes and human urine.Drug Metab Dispos
2006; in press.
5. Iribarne C, Berthou F, Carlhant D, Dreano Y, Picart D, Lohizic F, Riche C. Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Metab Dispos 1998; 26:257–260.
6. Goldsmith DR, Perry CM. Atazanavir. Drugs 2003; 63:1679–1695.
7. Friedland G, Andrews L, Schreibman T, Agarwala S, Daley L, Child M, 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.
8. Haas DW, Zala C, Schrader S, Piliero P, Jaeger H, Nunes D, et al
, for the Protocol AI424-099 Study Group. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 2003; 17:1339–1349.
9. Boffito M, Kurowski M, Kruse G, Hill A, Nelson M, Moyle G, et al
. Atazanavir enhances saquinavir hard gel concentrations in a ritonavir-boosted once daily regimen.
In: 11th Conference on Retroviruses and Opportunistic Infections
. San Francisco, 8–11 February 2004 [Abstract #607].
10. Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, von Moltke LL. Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro
. Drug Metab Dispos 2005; 33:764–770.
11. Reyataz (atazanavir) capsules [product information]. Princeton, NJ: Bristol-Myers Squibb Company; March 2004.
12. 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.