Lopinavir / ritonavir

Rifampin

Contraindicated.

No pharmaceutical opinion available for this interaction.

Mechanism

Rifampin may induce the hepatic metabolism (CYP 3A4) and decrease the plasma concentration of Lopinavir / ritonavir.

Lopinavir / ritonavir

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Risk of a possible development of resistance to antiretroviral class.

Recommendations

Alternative solution(s)

Rifampin

Pharmacodynamic effects

Increased risk of hepatotoxicity.

Recommendations

Choose an alternative.

Alternative solution(s)

Rifabutin either 150 mg QD, every 2 days or 3 times a week (see rifabutin with PIs) or choose an antibiotic that does not interact with PIs.

Monitor

Hepatotoxicity: elevation of hepatic transaminases by 3 to 5 fold, fatigue, unusual weakness, nausea, vomiting, anorexia, abdominal pains, pale stools, dark urine, jaundice.

Tests

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
Duration (days)
Cmax
Cmin
AUC 0-12h
Lopinavir / ritonavir
673 1444 2398
22 10/9 * 18
- - +
400/100 mg * 600/150mg/800/200 mg
BID BID BID
22 24 7/7 †
- 55% - 2%/- 7% ** - 28%/+ 13% ††
- 99% - 57%/+ 3% **  
- 75% - 16%/- 2% ** - 37%/+ 2% ††
Rifampin
673 1444 2398
22 10/9 * 18
- - +
600 mg 600 mg 600 mg
QD QD QD
10 14 (11-24) 21 (2-22)
     
     
     
Comment

Ref #673: Refers to the PK parameters of lopinavir.

Ref #1444: * All patients received lopinavir/r 400/100 mg BID for 15 days. For the next nine days group 1 received lopinavir/r 800/200 mg BID and group 2 lopinavir/r 400/400 mg BID.
** Ratios based on lopinavir concentrations on day 24 relative to day 10.
Nine subjetcs experimented an increase of hepatic enzymes of grade 2. Seven (21%) of them stopped the therapy. The study was made in such a way that it is difficult to determine if the hepatotoxicity is more frequent than with the use alone of rifampicin for the same population.

Ref #2178: Study not completed in 11 healthy patients receiving lopinavir/r 600/150 mg or 800/200 mg BID with rifampin 600 mg QD, because 10 subjects suffered from severe No/Vo and an increase of hepatic enzymes (AST/ALT).
Ref #2398 : † In the early study, lopinavir / ritonavir (400/100 mg BID) increased to 600/150 mg BID on day 9, and 800/200 mg BID on day 16.
†† Compared to lopinavir / ritonavir (400/100 mg BID) alone in early treatment.
With the standard dose of lopinavir/ritonavir (400/100 mg BID), the addition of rifampicin decreased lopinavir AUC and Cmax by 68% and 54%, respectively. Median lopinavir trough concentrations at baseline were 4.3 mg/L and decreased to 0.2 mg/L after 1 week of rifampicin. After the first lopinavir/ritonavir dose increase trough concentrations were 1.7 mg/L, and 3.7 mg/L after the second dose increase. There were no significant differences in lopinavir AUC, Cmax, C0h or C12h between baseline and the double dose. Treatment was generally well tolerated with only two subjects developing asymptomatic grade 3/4 alanine aminotransferase elevations. The authors concluded that doubling the dose of the tablet formulation of lopinavir/ritonavir overcomes the induction by rifampicin and there was less hepatotoxicity than previously seen in healthy volunteer studies.

Ref #2663 : In this study with 30 patients VIH+ in Vietnam, the association of "super-boosted" lopinavir/ritonavir (400/400 mg BID) with rifampicin (450-600 mg QD weight-based) seemed safe, though only 8 patients showed increased ALT. Authors concluded that this combination can be used as it appears to be well tolerated and until rifabutin becomes available in developing countries.

Ref #2894 : In a cohort of children receiving lopinavir/ritonavir plus additional ritonavir (to a ratio of LPV:RTV, 1:1), Lopinavir Cmin was similar between the 2 groups (n=15 children without and n=13 with rifampicin). In all 28 children, lopinavir Cmin was above the minimum therapeutic level (1 mg/L). As with adults this study found that additional ritonavir can be used to mitigate accelerated lopinavir elimination, overcoming the reduction of lopinavir levels caused by rifampicin.

Co-administration of rifampicin 600 mg QD with protease inhibitors such as darunavir/ritonavir, atazanavir/ritonavir and atazanavir alone also causes a decrease in AUC and Cmin of approximately 75% to 80%.

Ref #3116 : To increase the chance of achieving therapeutic serum levels and reduce the development of resistance and treatment failures some experts, as well as the CDC, recommend a 150mg QD dose. See rifabutin + PIs.

Reference
  • 673
    Norvir Prescribing Information, Abbott Laboratories, February 2010.
  • 1442
    la Porte CJL, Colbers EPH, Bertz R, et al. Pharmacokinetics (PK) of Two Adjusted Dose Regimens of Lopinavir/Ritonavir (LPV/r) in Combination with Rifampin (RIF) in Healthy Volunteers. 42nd ICAAC, American Society for Microbiology, September 27-30, 2002, San Diego, CA. Abstract A-1821.
  • 1444
    la Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004 May;48(5):1553-1560.
  • 2178
    Nijland HM, L’homme RF, Rongen GA et al. High incidence of adverse events in healthy volunteers receiving rifampicin and ajusted doses of lopinavir/ritonavir tablets. AIDS 2008;22:931-935.
  • 2377
    Lopinavir/ritonavir (Kaletra). Coorporation Abbvie, Quebec, Canada, 5 oct 2017.
  • 2398
    Decloedt EH, McIlleron H, Smith P, et al. Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets. Antimicrobial Agents and Chemotherapy, July 2011, 3195–3200.
  • 2434
    L'Homme R F, Nijland HM, Gras L, et al. Clinical experience with the combined use of lopinavir/ritonavir and rifampicin. AIDS. 2009;23(7):863-865.
  • 2663
    Colby D, Quang VM, Vinh Chau NV. Safety and Tolerability of Super-boosted Dosing of Ritonavir Administered with Lopinavir and Rifampin for HIV/TB Co-infection. Conference on Retroviruses and Opportunistic Infections, Seattle, 2012, Abstract 930.
  • 2894
    Ren Y, Nuttall JJC, Eley BS, et al. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Aquir Immune Defic Syndr, 2008 Apr 15; 47(5): 566-9.
  • 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.