Elvitegravir + Rifabutin = Precautionary

Effect on Concentration

Elvitegravir
Decrease
Applies within class?
No
Rifabutin
Unknown
Applies within class?
No

Pharmacologic Effects

Elvitegravir
Effect
N/A
Applies within class?
No
Rifabutin
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 17-Jul-2018

Summary

Sources

Boosted Elvitegravir versus Rifabutin ^

Study Design

Drug-drug interaction between cobicistat-boosted elvitegravir (EVG/co; 150/150mg) and rifabutin (150mg every other day) was evaluated in healthy volunteers.12 healthy subjects received EVG/co 150/150mg once daily for 10 days, followed by coadministration of EVG/co 150/150mg once daily plus rifabutin 150mg every other day for 13 days. After 10-day washout, subjects received rifabutin 300mg once daily for 13 days.

Study Results

Coadministration of EVG/co (150/150mg) and rifabutin 150mg decreased AUC and trough concentrations of EVG; geometric mean ratios (GMRs; EVG/co + rifabutin / EVG/co) [90% CIs] of AUC, Cmax and Cmin for EVG were 0.79 [0.74,0.85], 0.91 [0.84, 0.99] and 0.33 [0.27,0.40], respectively. PK of rifabutin was not significantly impacted when coadministered with EVG/co; GMRs (EVG/co + rifabutin / rifabutin) [90% CIs] of AUC, Cmax, and Cmin for rifabutin were 0.92 [0.83,1.03], 1.09 [0.99,1.20], and 0.94 [0.85.1.04], respectively. However, there was a 6.25-fold [5.08,7.69] increase in AUC [90% CI], 4.94-fold [4.04-6.04] increase in Cmin, and 4.84-fold [4.09, 5.74] increase in Cmax [90% CI] of the active metabolite of rifabutin (25-o-deascetyl-rifabutin), which resulted in 21% higher antimycobacterial activity compared with rifabutin 300mg once daily administered alone. [In a previous study which evaluated the PK interaction of ritonavir-boosted EVG and RBT (n=18). Participants were given RBT 300mg alone, EVG/ritonavir 300/100 mg alone, or in combination with a reduced dose of rifabutin 150mg QD. Results from this study showed equivalent exposures of EVG/ritonavir +RBT relative to each of them alone, and the PK of EVG and RBT were within the defined no-effect boundary. Hpowever, AUC and Cmax of 25-O-desacteylrifabutin increased 9.5- and 5.4-fold respectively, increasing the antimycobacterial activity by 50%.]

Study Conclusions

According to the guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents and the latest prescribing information for elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild®) published in December 2014, coadministration of EVG/co and rifabutin is not recommended, as this may lead to decreased concentrations of EVG resulting in reduced virologic response and possible viral resistance. If concomitant use is necessary, monitor closely for reduced EVG efficacy including the loss of virologic response and development of antiretroviral resistance. Additionally, when EVG is administered with cobicistat or as the combination product containing elvitegravir/cobicistat/emtricitabine/tenofovir, close monitoring for rifabutin side effects such as neutropenia is warranted; adjust dose accordingly as this may lead to increased rifabutin plasma concentrations due to other components of the combination.

References

Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the hiv integrase inhibitor elvitegravir. Clinical Pharmacokinetics. 2011; 4: 229-244.