Darunavir / ritonavir

Rifabutin

Dosage adjustment is recommended.

No pharmaceutical opinion available for this interaction.

Mechanism

Darunavir / ritonavir can inhibit the metabolism (CYP 3A4) and increase the plasma concentration of Rifabutin.

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

Darunavir / ritonavir

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Recommendations

No a priori dosage adjustment is recommended.

Monitor the clinical efficacy and appearance of adverse effects.

Alternative solution(s)

Dolutegravir 50 mg QD or raltegravir 400 mg BID or raltegravir HD 1200 mg QD

Rifabutin

Pharmacodynamic effects

Possible increase of adverse effects.

Recommendations

Dose reduction suggested of up to 75% (e.g., 150 mg every other day).

To increase the probabilities of achieving therapeutic serum levels and reduce the development of resistance and treatment failures some experts, as well as the DHHS, recommend a rifabutin dose of 150mg QD.

Monitor closely clinical efficacy and appearance of adverse effects.

Alternative solution(s)

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

Darunavir plasma level

Pharmacokinetic parameters
Parameters
Reference number
# patients
Dose
Frequency
HIV
Cmax
Cmin
AUC
Duration (days)
AUC 0-12h
Rifabutin
2258 2258 2415 2415
11   27 27
300 mg 150 mg 300 mg 150 mg
OD X1 OD Q48h
+ + - -
       
       
       
    12 12
       
Darunavir / ritonavir
2258 2258 2415 2415
11   27  
600/100 mg   600/100 mg  
BID   BID  
+   -  
+ 42%/± 0%      
+ 75%/± 0%      
+ 57%/+ 66%      
    12  
    + 57%/+ 66%  
Comment

* Rifabutin AUC was comparable when given at the standard dose alone or at the reduced dose in combination.

Several studies were initially done with healthy subjects with the combination of protease inhibitors and rifabutin. These studies demonstrated that a dose of rifabutin 150 mg 3 times/week associated with protease inhibitors was approximately equivalent to a dose of rifabutin 300 mg QD.
Subsequently, studies in subjects co-infected with HIV and tuberculosis demonstrated that the dose of 150 mg 3 times/week was insufficient for some subjects. Therefore, the dose of rifabutin 150 mg QD in combination with PIs is currently recommended in the guidelines.

Rifabutin dosage at steady-state (t1/2 normal; 25hrs) : targeted therapeutic index of 0.3-0.9μg/ml 3-4 post dose (Cmax) and a dose reduction may be necessary from 1μg/ml depending on the clinical context.

Ref #3117 : Concomitant administration of a protease inhibitor and rifabutin increases the plasma concentrations of rifabutin and 25-O-desacetyl rifabutin. The addition of a protease inhibitor slightly increases the concentrations of rifabutin, but increases the concentrations of 25-O-deacetyl rifabutin by 5 to 10-fold. In return, rifabutin does not significantly affect the plasma concentrations of protease inhibitors.

Ref #2258: Coadministration of rifabutin (150 mg every other day) and darunavir/ritonavir (600/100 mg twice daily) was studied in 11 subjects. The AUC, Cmax and Cmin of darunavir increased by 57%, 42% and 75%, respectively. When compared to rifabutin 300 mg once daily alone, rifabutin AUC and Cmax decreased by 7% and 28%, but Cmin increased by 64%. The AUC, Cmax and Cmin of 25-O-desactyl rifabutin increased by 9.81-fold, 4.77-fold and 27.1-fold, respectively. Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day).

Ref #2415: This was a randomised 3-way crossover study in healthy volunteers of darunavir/ritonavir alone (600/100 mg twice daily), rifabutin alone (300 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) plus rifabutin (150 mg every other day). Each treatment period lasted 12 days with full pharmacokinetic analysis on day 13. The main findings were:
AUC0-12 of darunavir and ritonavir increased by 57% and 66%, respectively, in the presence of rifabutin.
Rifabutin exposure was comparable when given once daily alone or once every other day with darunavir/ritonavir.
Exposure of the active metabolite (25-O-desacetyl rifabutin) was considerably enhanced (by 9.8-fold) with darunavir/ritonavir and consequently parent + metabolite exposure increased 1.6-fold.
Adverse events were more common with combined treatment. Note, 18/27 subjects discontinued prematurely.
It is not recommended to conduct further studies of this combination in healthy subjects.
The recommendation in patients is to dose adjust rifabutin to 150 mg every other day with careful monitoring for rifabutin-associated adverse events.

Reference
  • 2258
    Sekar VJ, et al. Pharmacokinetic interaction between darunavir in combination with low-dose ritonavir and rifabutin.48th ICAAC Meeting, Washington, 2008. Drug Interaction Report. Abstract H-4053.
  • 2386
    Darunavir (Prezista), Janssen, Ontario, Canada, 23 mai 2018.
  • 2415
    Sekar V, Lavreys L, Van de Casteele T, et al. Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob Agents Chemother, 2010, 54(10): 4440-4445.
  • 122
    Ritonavir (Norvir), Corporation AbbVie, Quebec, Canada, 25 septembre 2018.
  • 1096
    Rifabutin (Mycobutin), Pfizer, Québec, Canada, 22 juin 2015.
  • 2449
    Naiker S, Conolly C, Weisner L et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th Conference on Retroviruses and Opportunistic Infections, 2011 : Abstract 650.
  • 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.
  • 3151
    AIDS info, Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Disponible : https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Publié le 17 oct. 2017. Consulté le 11 janvier 2018.