Ritonavir

Rifabutin

Dosage adjustment is recommended.

No pharmaceutical opinion available for this interaction.

Mechanism

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 Ritonavir.

Ritonavir

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Therefore, resulting in loss of therapeutic effect of associated IP.

Recommendations

No a priori dosage adjustment is recommended.

Monitor for clinical efficacy and adjust the dosage if necessary.

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

Associated PI plasma level

Pharmacokinetic parameters
Parameters
Reference number
# patients
AUC 0-24h
Cmax
Cmin
Dose
Frequency
Duration (days)
Rifabutin
307
5
+ 4 x
+ 2.5 x
+ 6 x
150 mg
QD
16
Ritonavir
307
5
 
 
 
500 mg
BID
10
Comment

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 #307: The AUC 0-24h, Cmax and Cmin of 25-O-desacetyl rifabutine increased by 35x, 16x and 200x, respectively. Because ritonavir may induce its own metabolism, it is possible to observe an increase in rifabutine metabolism right after stopping ritonavir.

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.

Reference
  • 122
    Ritonavir (Norvir), Corporation AbbVie, Quebec, Canada, 25 septembre 2018.
  • 307
    Cato A 3rd, Cavanaugh J, Shi H et al. The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther 1998;63:414-421.
  • 328
    Gallicano K, Khaliq Y, Seguin I et al. A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in HIV patients. 8th Annual Canadian Conference on HIV/AIDS Research 1999. Abstract B-204.
  • 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.
  • 2449
    Naiker S, Conolly C, Weisner L, Kellerman T, Reddy T et al.Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol. 2014; 15: 61.
  • 1096
    Rifabutin (Mycobutin), Pfizer, Québec, Canada, 22 juin 2015.
  • 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.