No pharmaceutical opinion available for this interaction.
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.
2C9, 2C19, 2C8 (moderate), UGT (moderate)
3A4 (strong), 2D6 (moderate), 2B6 (probable)
Possible decrease of clinical efficacy.
No a priori dosage adjustment is recommended.
Monitor the clinical efficacy and appearance of adverse effects.
Dolutegravir 50 mg QD or raltegravir 400 mg BID or raltegravir HD 1200 mg QD
3A4, cholibestérase, Un des métabolites est métabolisé CYP 3A4 (25-O-desacetyl rifabutine = activité similaire à la rifabutine)
Possible increase of adverse effects.
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.
Rifabutin adverse effects : rash, taste alterations, anorexia, nausea, insomnia, facial paralysis, twitching, peripheral neuritis, neutropenia, thrombocytopenia, arthralgia, uveitis, elevation of liver function tests.
Viral load HIV
Darunavir plasma level
|300 mg||150 mg||300 mg||150 mg|
|600/100 mg||600/100 mg|
|+ 42%/± 0%|
|+ 75%/± 0%|
|+ 57%/+ 66%|
|+ 57%/+ 66%|
* 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.