Atazanavir (Reyataz), boosted by low dose ritonavir (Norvir) appears to interact with the opiate substitute, buprenorphine. Doctors from Connecticut in the USA report a series of cases demonstrating the interaction in the March 21st edition of AIDS and recommend, “the use of buprenorphine in combination with ritonavir and atazanavir should be undertaken cautiously.”
Three cases of an interaction between atazanavir/ritonavir and buprenorphine are reported by the investigators. In all three cases the patients were also taking drugs from the nucleoside/nucleotide reverse transcriptase inhibitor class, but existing pharmacokinetic knowledge did not provide any reason for the doctors to expect an interaction between any of these antiretrovirals and buprenorphine.
The first case involved an individual who after two days treatment with 14mg/day of buprenorphine was started on once-daily HIV therapy consisting of enteric coated ddI (250mg), tenofovir (300mg) and atazanavir/ritonavir (300/100mg). The next day the patient experienced daytime sleepiness, and reduced mental function. The patient was initially offered increased counselling, but after two weeks the daily dose of buprenorphine was reduced to 8mg with a reduction in sedative symptoms within a week.
HIV therapy consisting of enteric-coated ddI, tenofovir, and atazanavir/ritonavir was also being prescribed to the second patient who complained of feeling ‘doped out’ two days after starting treatment with a buprenorphine dose of 8mg a day. Dosing of the opiate substitute was reduced to being of alternate days with an improvement in symptoms.
Whilst in prison, the third patient had been taking stable antiretroviral therapy consisting of once-daily 3TC (300mg) with tenofovir (300mg) and atazanavir (400mg). After release, the dose of atazanavir was changed to 300mg boosted by 100mg of ritonavir. Treatment with 8mg of buprenorphine was also initiated at a dose of 8mg a day. However, the patient complained of dizziness, feeling ‘high’ and the dose of buprenorphine was reduced to 8mg ever other day. Craving for opiates led to the dose being increased to 12mg per day that caused sleepiness similar to that observed in the other two patients. With support and counselling, however, tolerance developed.
“This small case series is the first to suggest and document possible clinical drug interactions between buprenorphine and two protease inhibitors known to inhibit [the liver enzyme] CYP3A4.”
A small test tube study had previously shown an increase in buprenorphine levels due to the blocking of its metabolism when used with ritonavir. Both drugs use the CYP3A4 pathway. The investigators speculate that atazanavir also inhibited a secondary pathway used to metabolise buprenorphine.
Bruce RD et al. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS 20: 783 – 784, 2006.