Lopinavir / ritonavir

Rifabutin

Dosage adjustment is recommended.

No pharmaceutical opinion available for this interaction.

Mechanism

Lopinavir / 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 Lopinavir / ritonavir.

Lopinavir / ritonavir

Pharmacodynamic effects

Possible decrease of clinical efficacy.

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

Lopinavir plasma level

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
Duration (days)
AUC
Cmax
Cmin
Lopinavir / ritonavir
2377 1318 2365 2449 2449 2450
12 14 10 16 16 17
- - + + +  
400/100 mg 400/100 mg 400/100 mg 400/100 mg 400/100 mg 400/100 mg
BID BID BID BID BID BID
10 20 28 30 30  
  + 17%        
  + 8%        
  + 20%        
Rifabutin
2377 1318 2365 2449 2449 2450
12 14 10 16 16 17
- - + + +  
150 mg 150 mg 150/300 mg 150 mg 150 mg 150 mg
QD QD TIW TIW QD QD
10 10 28 30 30  
+ 203% *   + 34% - 20% † + 60% †  
+ 112% *   - 19% - 50% † ± 0% †  
+ 390% *     + 20% † + 170% †  
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 #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 #2377: * Compared to rifabutin 300 mg QD alone.
AUC, Cmax and Cmin of 25-O-desacetyl rifabutin increased by 48-, 24-, and 95-fold, respectively.

Ref #2301: 15 healthy HIV-adults were selected to receive rifabutin 150 mg QD for 10 days in period 1, followed by rifabutin 150 mg 3 times per week during 12 days. The study had to be stopped after the addition of rifabutin to lopinavir/ritonavir because of side effects. The author concludes that in healthy volunteers co-administration of rifabutin 150 mg twice weekly with LPV/r significantly increased rifabutin and was associated with sides effects.

Ref #2365: In this study with 10 HIV patients with tuberculosis, the concentration of the rifabutin was compared with its active métabolite the 25-O-desacetyl rifabutin:
A) Rifabutin 300 mg three times a week without the lopinavir/ritonavir
B) rifabutin 150 mg 3 times week + lopinavir/ritonavir and then if the Cmax was lower than 0,3 ug/ml (lower limit for treatment efficacy), the dose of rifabutin was increased to 300 mg 3 times weekly.
With rifabutin 300 mg 3 times a week without lopinavir/ritonavir: 5/10 had Cmax lower than the aimed values. After the addition of the lopinavir/ritonavir and a decrease of the dosage of rifabutin to 150 mg 3 times per week, 9/10 had a Cmax of rifabutine under the aimed values. In spite of an increase of the dosage of the rifabutine to 300 mg 3 times a week for 8 patients, the majority of the Cmax were lower than the aimed values.
Regarding the side effects, one patient developed a neutropenia under treatment (on the 21th day with 150mg BID), 2 patients had elevations in liver enzymes levels and two had an immune reconstitution inflammatory syndrome (IRIS). Authors recommend monitoring rifabutin concentrations of during the treatment in order to obtain efficient concentrations.

Ref #2449 : † Compared to rifabutin 300 mg QD.
Rifabutin 150 mg three times per week (TIW) compared with rifabutin 150 mg QD : AUC -60%; Cmax -50% and Cmin -50%.
86% of patients on the TIW rifabutin arm had an AUC < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance. Plasma 25-O-desacetylrifabutin concentrations increased by 5-fold with rifabutin TIW and by 15-fold with rifabutin QD. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities.

Conclusion of the authors: with lopinavir/ritonavir, the dose of rifabutin 150 mg once a day allows to obtain a Cmax of rifabutin that are inside the therapeutic interval (300-900 ng/ml).

Ref #2450: In this study with 17 patients HIV+/TB, the pharmacokinetics of the rifabutin 300 mg QD were compared with those of rifabutine 150 mg QD with lopinavir/ritonavir (two measures: one after 2 weeks and the other one after 6 weeks). A bigger increase of the active metabolite of the rifabutin was observed (25-O-desacetyl rifabutin) vs rifabutin, probably related with CYP3A4 inhibition by lopinavir/ritonavir.
Conclusion of the authors: by considering the sum of the rifabutin and the metabolite (25-O-desacetyl rifabutin), the concentration obtained with the rifabutin 150 mg QD with lopinavir/ritonavir is comparable to the dose of rifabutin 300 mg QD. In this study the dose of rifabutin 150 mg QD with the lopinavir/ritonavir was effective and well tolerated.

Ref #2355: Cases of M Tuberculosis resisting to rifampin were reported with rifabutin 150 mg every 2 days or 3 times per week with HIV+ patients treated with lopinavir/r and atazanavir/r.

Reference
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  • 1318
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