Raltegravir

Rifampin

Dose adjustment and closer monitoring are required.

No pharmaceutical opinion available for this interaction.

Mechanism

Rifampin can increase the metabolism (UGT 1A1) and decrease the plasma concentration of Raltegravir.

Raltegravir

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Recommendations

If this combination is used, increase the dose of raltegravir to 800 mg BID. However, this dose increase does not counteract totally the pharmacokinetic interaction, a decrease of raltegravir Cmin is still observed.

Unknown clinical meaning. Use with caution.

Closely monitor clinical effectiveness.

Raltegravir HD 1200 mg QD : Association not recommended.

Alternative solution(s)

Rifampin

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Rifabutin 300 mg QD

Monitor

Tests

Viral Load

Raltegravir plasma level

CD4+

Pharmacokinetic parameters
Parameters
Reference number
Dose
Frequency
# patients
HIV
AUC
Cmax
C12h
Duration (days)
Rifampin
2373 2373 2702 2152 2936
600 mg 600 mg 600 mg 600 mg 900 mg
OD QD QD QD TIW
17   16 9 16
-   + - -
         
         
         
        38 †
Raltegravir
2373 2373 2702 2152 2936
400 mg 800 mg * 400 mg 400 mg 400 mg/800 mg
QD BID* BID x 1 BID
17   21 9 16
-   + - -
- 39% + 27% * - 6% - 40% + 8%/ + 84% ††
- 62% + 62% * - 1% - 38% + 16%/ + 76% ††
- 60% - 53% * - 31% - 61% - 40%/ - 11% ††
        43 †
Comment

Co-administration of raltegravir HD 1200 mg QD and rifampin has not been studied.

Ref #2373 : The first part of the study compared the immediate effect of 600 mg of rifampin over a unique dose of 400 mg of raltegravir. * The second part of the study compared the administration of 600 mg QD of rifampicine and 800 mg BID of raltegravir with regard to the administration of 400 mg BID of raltegravir alone. The authors conclude that doubling the raltegravir dose to 800 mg when coadministrated with rifampin allows to compensate for the metabolic induction of raltegravir as for the exposure (AUC), but the trough concentrations remains at the lower limit clinically accepted. Coadministration of rifampin and raltegravir is not contraindicated; however caution should be used.

Ref #2702 : An ANRS study presented at CROI 2013 (Abstract 539) demonstrated that treatment with efavirenz compared to raltegravir 800 mg BID for the treatment of HIV patients co-infected with tuberculosis was comparable to the point of view of efficacy and safety (30% of patients in the two groups have developed adverse reactions of grade 3).

A sub-analysis of drug interactions was published at the same conference CROI 2013. This summary showed the results of a study of drug interactions. Patients were randomized to receive either raltegravir 400 mg twice daily or 800 mg twice daily. The pharmacokinetic results were highly variable, but there was a trend toward lower concentrations of RAL (Cmax, Cmin, AUC) when it was given in 400 mg BID with rifampin. These effects were lower in the group receiving raltegravir 800 mg BID.

Ref #2936 : † RAL 400 BID for 5 days, then 33 days of RAL (400mg bid) + RIF(900mg thrice weekly), then 5 days of RAL (800mg bid) + RIF as above.
†† Versus RAL 400mg bid without RIF.
Importantly, a significant proportion of subjects taking RAL 400mg bid (4/16) had C12h at/below the upper bound of the lowest quartile from QDMRK, associated with blunted therapeutic response. Similar findings were observed with RAL + daily RIF in patients suggesting RIF induction of RAL is comparable between daily and intermittent RIF. In the absence of definitive clinical efficacy data to suggest otherwise, doses of RAL800mg bid with thriceweekly RIF are well tolerated and yield higher AUCs and comparable C12 compared to RAL alone.

Ref #2962 : In this study, 153 received randomly raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily. At week 24, virological suppression was achieved in 39 patients (76%) in the raltegravir 400 mg group, 40 patients (78%) in the raltegravir 800 mg group, and 32 patients (63%) in the efavirenz group. The adverse-event profile was much the same across the three groups. The authors conclude that raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis.

Reference
  • 2215
    Iwamoto M, et al. Rifampin modestly reduces plasma levels of MK-0518. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2006, abstract 299.
  • 2256
    Brainaird DM, et al. Doubling the dose of raltegravir does not increase trough levels in the presence of rifambin. 48th ICAAC Meeting, Washington, 2008. Drug Interaction Report. Abstract A-964
  • 2373
    Wenning L, Hanley WD, Brainard DM et al.Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir, Antimicrobial agents and chemotherapy, July 2009, p. 2852–2856
  • 2702
    Sauvageon H, Grinsztejn B, Arnold V, et al. Pharmacokinetics of Two Doses of Raltegravir in Combination with Rifampin in HIV-TB Co-infected Patients, an ANRS 12 180 Reflate TB Sub-study. CROI 2013, Atlanta, March 3-6 2013. Abstract #539.
  • 2725
    Burger DM, Magis-Escurra C, van den Berk GEL, and al. Pharmacokinetics of double-dose raltegravir in two patients with HIV infection and tuberculosis. AIDS 2010; 24(2): 328-30.
  • 2666
    Weiner M, Egelund EF, Engle M, Kiser M et al. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. J Antimicrob Chemother 2014; 69(4): 1079-85.
  • 2667
    Lee LS, Hee KH, Yao Z, et al. Induction and inhibition of raltegravir metabolism in healthy volunteers. 13th International workshop on clinical pharmacology of HIV therapy, Barcelona, April 2012, Abstract P_07.
  • 2152
    Raltegravir (Isentress, Isentress HD), Merck, Quebec, Canada, 21 juin 2017.
  • 2857
    Raltegravir (Isentress), European public assessment report (EPAR) Product Information, London, United Kingdom, sept 2013.
  • 2936
    Reynolds HE, Chrdle A, Egan D, Chaponda M, et al. Effect of intermittent rifampicin on the pharmacokinetics and safety of raltegravir. J Antimicrob Chemother, 2015, 70: 550-554.
  • 2962
    Grinsztjen B, De Castro N, Arnold V, Veloso VG, Morgado M et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014 Apr 9. pii: S1473-3099(14)70711-X.
  • 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.