 |
|
|
| |
Antiretroviral Interactions With Anti-TB Drugs
|
| |
| |
Written for NATAP: A report from the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dec 2005
Mark Mascolini
The anti-tuberculosis (TB) drugs rifampin and rifabutin may have nasty interactions with protease inhibitors (PIs) or nonnucleosides because many of these medications depend on the same enzymes for their metabolism. Separate research groups found that rifampin cannot be given with standard-dose atazanavir/ritonavir, that rifampin cuts nevirapine levels in Thai patients (who typically weigh less than Western patients), and that a lower-than-usual dose of rifabutin may work acceptably with fosamprenavir/ritonavir.
Avoid rifampin with atazanavir/ritonavir
A study in healthy volunteers without HIV infection showed that unboosted atazanavir should not be prescribed with the anti-TB drug rifampin, because rifampin dramatically cuts levels of this PI. Josep Mallolas and colleagues at Barcelona's Hospital Clinic surmised that boosting atazanavir with low-dose ritonavir would overcome this dangerous drug interaction [1]. But it didn't.
The rationale behind the Barcelona study looked strong. Atazanavir gets metabolized (processed and eliminated from the body) largely via an enzyme called CYP3A4. Rifampin ranks as one of the strongest inducers of CYP3A4. That means people taking rifampin have more CYP3A4, and that results in faster processing and elimination of atazanavir. So atazanavir levels rarely get high enough when taken by a person also taking rifampin.
Among the PIs, ritonavir is the strongest CYP3A4 inhibitor. Adding a low dose of ritonavir to most PIs hikes levels of the second PI, because the second PI's metabolism slows down when there's not as much CYP3A4 around.
To see whether the standard dose of atazanavir/ritonavir (300/100 mg once daily) would compensate for rifampin's impact on atazanavir, Mallolas planned to recruit 8 people taking a triple-nucleoside regimen as well as 300 mg of rifampin daily and other anti-TB drugs. Everyone already had a viral load below 200 copies/mL. Then atazanavir/ritonavir got added to their regimen.
Three weeks later, Mallolas measured atazanavir concentrations. In all of the first 3 people who signed up for the study, atazanavir levels remained far below those recommended for this PI. Pharmacologists could measure no atazanavir in blood samples from these 3 people at the end of the dosing interval. Ritonavir's inhibition of CYP3A4 didn't overcome rifampin's induction of that enzyme.
Mallolas and coworkers ended the study there and advised colleagues not to mix atazanavir/ritonavir with rifampin.
Low nevirapine levels in Thai patients taking rifampin
The anti-TB drug rifampin lowered nevirapine trough concentrations about 18% in a study of 140 Thai patients combining the two drugs [2]. The finding cannot be translated into advice on pairing the drugs in Western populations, because most of the Thais studied were very light in comparison. Three quarters of the Thais weighed less than 60 kg (132 pounds).
Weerawat Manosuthi from the Bamrasnaradura Institute in Nonthaburi studied 70 people with active TB who had taken rifampin for more than 1 month when they began their first antiretroviral regimen—standard-dose nevirapine plus d4T and 3TC. A control group included 70 people who started the same antiretrovirals but were not taking rifampin.
Median pretreatment CD4 counts were low—33.5 cells/mm3 in the rifampin group and 29.0 cells/mm3 in the no-rifampin group. And most study participants were young, averaging 36 years of age.
After 12 weeks of antiretroviral therapy, nevirapine levels 12 hours after dosing averaged 5.4 micrograms/mL among people taking rifampin and 6.5 micrograms/mL in those not taking rifampin, a significant difference (P = 0.048). Although the average nevirapine level in rifampin-treated people lay above the 50% inhibitory concentration for nevirapine, levels of the nonnucleoside probably fell too low in some people.
In a statistical analysis adjusted for several factors that may affect nevirapine levels, only rifampin emerged as an independent predictor of low nevirapine concentrations.
Whether the same interaction occurs in people who weigh more than this Thai group requires further study.
Low-dose rifabutin option with fosamprenavir/ritonavir
In a study of healthy volunteers without HIV infection, Glaxo researchers found that a lower-than-standard dose of the anti-TB drug rifabutin has acceptable interactions with fosamprenavir/ritonavir dosed at 700/100 mg twice daily [3]. But one third of these healthy people had to drop out of the study when taking the lower rifabutin dose, usually because of side effects.
For 2 weeks the Glaxo team gave 22 volunteers either the standard rifabutin dose—300 mg daily—or 150 mg of rifabutin every other day plus 700/100 mg of fosamprenavir/ritonavir twice daily. After a period taking no drugs, the volunteers returned and took the regimen they had not tried before.
Because ritonavir inhibits the CYP3A4 enzyme, it drives rifabutin level higher by slowing its metabolism and elimination from the body. But when people took rifabutin every other day with fosamprenavir/ritonavir, 48-hour levels and trough concentrations of the anti-TB drug proved equivalent to those attained with the standard daily dose given without the PIs.
Rifabutin's peak concentration was 14% lower with every-other-day dosing plus PIs than with standard daily dosing without PIs. But that difference probably has no clinical consequence.
Peak concentrations of rifabutin's major metabolite rose 11-fold and its 48-hour exposure rose 6-fold with the low-dose-plus-PI regimen compared with standard-dose rifabutin without fosamprenavir/ritonavir. Those gains are not worrisome because the metabolite levels reach only about 10% of the levels attained by rifabutin itself. Total anti-TB exposure—the sum of rifabutin exposure and its metabolite's exposure—jumped 64% with the lower rifabutin dose plus the PIs compared with 300 mg of rifabutin daily without the PIs.
Levels of amprenavir—the end product of fosamprenavir in the body—rose about one third with the low dose of rifabutin when compared with people in earlier studies who took the same dose of fosamprenavir/ritonavir without rifabutin.
The Glaxo team recommended giving rifabutin at a dose of 150 mg every other day when it must be combined with 700/100 mg of fosamprenavir/ritonavir twice daily. But some people may find even that lower dose hard to tolerate. Seven of 22 volunteers (32%) dropped out of the study when taking 150 mg of rifabutin every other day and fosamprenavir/ritonavir, 5 of them (23%) because of side effects. These treatment-limiting toxicities were rash in 3 people, nausea in 1, and myalgia, fever, plus a high white cell count in another.
Mark Mascolini writes about HIV infection
References
1. Mallolas J, Nomdedeu M, Soriano A, et al. Pharmacokinetic interaction between rifampin and the combination of atazanavir and low-dose ritonavir in HIV-infected patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract A-1202.
2. Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Comparison of plasma levels of nevirapine, liver function test, virological and immunological outcomes in HIV-infected patients receiving and not receiving rifampicin: preliminary results. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-413.
3. Chen Y, Ford SL, Shelton MJ, et al. Pharmacokinetic interaction between rifabutin and fosamprenavir/ritonavir in healthy subjects. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract A-1199.
|
|
| |
| |
|
|
|
|
|
