Elvitegravir / Cobicistat

Rifabutin

Not recommended association.

No pharmaceutical opinion available for this interaction.

Mechanism

Rifabutin can induce the metabolism (CYP 3A4) and decrease the plasma concentration of Elvitegravir / Cobicistat.

Elvitegravir / Cobicistat may possibly inhibit the metabolism (CYP 3A4) and consequently increase the plasma concentration of Rifabutin.

Elvitegravir / Cobicistat

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Recommendations

Avoid association. Choose an alternative.

Alternative solution(s)

Dolutegravir 50 mg QD or raltegravir 400 mg BID or raltegravir HD 1200 mg QD : see dolutegravir + rifabutin or raltegravir + rifabutin.

Rifabutin

Pharmacodynamic effects

Increase of adverse effects.

Recommendations

Avoid association.

Alternative solution(s)

Antibiotic not interacting with elvitegravir/cobicistat.

Monitor

Rifabutin adverse effects : rash, taste alterations, anorexia, nausea, insomnia, facial paralysis, twitching, peripheral neuritis, neutropenia, thrombocytopenia, arthralgia, uveitis, elevation of liver function tests.

Tests

Rifabutin

Blood count

Liver function

CD4+

Viral load HIV

Elvitegravir plasma level

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
AUC
Cmin
Cmax
Elvitegravir / Cobicistat
2721 3067
12 14
- -
150/150 mg 150/150 mg
QD QD/BID
- 21%  
- 67% + 59%
- 9%  
Rifabutin
2721 3067
12 14
- -
150 mg 150 mg
QOD QOD
+ 525% *  
+ 394% * + 41%
+ 384% *  
Comment

Ref #2721 : * Refer to 25-O-desacetyl rifabutin.
There was a similar exposure to rifabutin. The antimycobacterial effect observed was 21% higher with elvitegravir/cobicistat association. Further studies are in progress.

Ref #3067 : Twice daily administration of cobicistat with once daily elvitegravir mitigated the effect of rifabutin induction upon their coadministration. Elvitegravir and rifabutin exposures (AUC and Cmax) were within the predefined boundary, while EVG and RFB Cmin were higher, 59% for elvitegravir and 41% for rifabutin. Importantly, elvitegravir Cmin, the parameter best associated with antiviral activity, was >10-fold above the IC95 (45 ng/mL). Consistent with rifabutin coadministration with boosted-protease inhibitor regimens, the exposure of 25-O-desacetylrifabutin were markedly higher (~12-fold). However, the total increase in antimycobacterial activity was less than 2-fold.

Ref #3117 : To optimize the monitoring for rifabutin, dosage of this agent, at equilibrium (t1/2 normal; 25hrs), may be necessary. The targeted therapeutic index of 0.3-0.9μg/ml 3-4 post dose (Cmax) and a dose reduction may be necessary from 1 μg/ml depending on the clinical context.

Comment
Reference
  • 2570
    Elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild), Gilead, Ontario, Canada, 17 septembre 2018.
  • 2721
    Ramanathan S, Wang H, Stondell T, et al. Pharmacokinetics and drug interaction profile of cobicistat boosted-elvitegravir with atazanavir, rosuvastatin or rifabutin. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona, Spain. Abstract O_03.
  • 3067
    Custodio JM, Shao Y, Begley R, Graham H, Vimal M et al. Pharmacokinetics of boosted-elvitegravir in combination with rifabutin, utilizing twice daily administration of cobicistat to overcome induction. 20th International AIDS Conference (IAC), Melbourne, Australia 2014, Abstract THPDB0102.
  • 3116
    Center for Disease Control and prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. Disponible: http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/recommendations03.htm Publié le 22 sept 2014. Consulté le 11 janvier 2018.
  • 3117
    Regazzi M, Carvalho AC, Villani P, Matteelli A. Treatment Optimization in Patients Co-Infected with HIV and Mycobacterium tuberculosis Infections: Focus on Drug–Drug Interactions with Rifamycins. Clinical Pharmacokinetics, June 2014, 53 (6), 489-507.
  • 1096
    Rifabutin (Mycobutin), Pfizer, Québec, Canada, 22 juin 2015.
  • 3281
    Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya), Gilead, Ontario, Canada, 6 août 2021.