Atazanavir / ritonavir

Rifabutin

Dosage adjustment is recommended.

No pharmaceutical opinion available for this interaction.

Mechanism

Atazanavir / 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 Atazanavir / ritonavir.

Atazanavir / 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

Atazanavir plasma level

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Dose
Frequency
Duration (days)
Food
AUC
Rifabutin
504
30
-
150 mg
QD
14
+
 
Atazanavir / ritonavir
504
30
-
400-600 mg/0-100 mg
QD
14
+
+/- 0%
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 #2288 : * In comparison to the patient group (N=15) receiving rifabutin 150 mg BID alone. When the unique dose per day of rifabutin is compared to rifabutin 150 mg, twice a week with atazanavir/ritonavir, an increase of the AUC and Cmin of the 25-0-desacetyl rifabutin of 10,9 and 11,5 times is observed. Results of the study showed that the concentrations with rifabutin 150 mg twice a week are higher than with rifabutin 150 mg BID and the activity measured is the same as with the dosage of rifabutin 300 mg BID. The author suggests to monitor neutrophils with this association.

Ref#504: (A) 400 mg ATV+150 mg RIF qd; (B) 600 mg ATV+150 mg RIF qd; or (C) 400 mg ATV+ 100 mg RTV QD + 150 mg RIF. ATV exposure at 400 mg did not change with RIF (Treatment A), but was 2- to 3-fold higher with Treatments B and C. The AUC of RIF was comparable across treatments but 2.5 fold higher than literature values for a standard 300-mg dose.

Ref #2329: Case 1: A 42-year-old man tested positive for HIV infection in 1999; his CD4 cell count was 223 cells/mm3. He remained healthy until March 2005, when drug-susceptible pulmonary tuberculosis was diagnosed. He received directly observed therapy. His treatment consisted of 300 mg of isoniazid QD, 600 mg of rifampin QD, 1500 mg of pyrazinamide QD, and 800 mg of ethambutol QD for 2 months followed by intermittent doses of 900 mg of isoniazid and 600 mg of rifampin, mostly thrice weekly, for 4 months. Smear and culture test results were negative after the first month of therapy. He remained off of HAART. In January 2006, he presented with fever, cough, and a CD4 cell count of 3 cells/mm3. Sputum samples were positive for acid-fast bacilli on the basis of smear microscopy. Drug-susceptible M. Tuberculosis grew from sputum and blood samples. He resumed directly observed therapy with 600 mg of rifampin QD, 300 mg of isoniazid QD, and 2000 mg of pyrazinamide QD for 2 months followed by 300 mg of isoniazid QD and 600 mg of rifampin QD; culture and smear test results were negative after 3 weeks of therapy. In May 2006, HAART was initiated with atazanavir/ritonavir 300/100 QD , 300 mg of zidovudine BID, and 150 mg of lamivudine BID. Simultaneously, rifabutin 150 mg every other day replaced rifampin 600 mg QD. Because of an inadequate HIV virologic response, lopinavir/ritonavir 400/100 mg BID replaced atazanavir/ritonavir 300/100 mg QD. Tuberculosis therapy was stopped in July 2006 after nearly 7 months. While receiving the new HAART, the patient’s CD4 cell count increased to 111 cells/mm3, and he began to feel better. However, in November 2006, he had fevers and experienced weight loss. Despite having repeatedly normal chest radiograph findings, the patient’s blood and sputum samples from December 2006 yielded rifampin resistant M. Tuberculosis on culture. The identity of the isolates from all 3 episodes was confirmed. Therapeutic drug monitoring was done to optimize therapy for the unexpected second tuberculosis relapse. The serum concentration after 300 mg of isoniazid was 1.09 mg/mL (range, 3–6 mg/mL), and the serum concentration after 1200 mg of ethambutol was 1.18 mg/mL (range, 2–6 mg/mL); the serum concentrations of the other concurrent drugs (ie, pyrazinamide, streptomycin, and moxifloxacin) were within their therapeutic ranges.


Case 2: A 47-year-old man tested positive for HIV infection in 1992; his CD4 cell count was 1700 cells/mm3. He remained healthy without HAART. In July 2006, with a CD4 cell count of 30 cells/mm3, his blood, urine, and sputum samples yielded drug-susceptible M. Tuberculosis on culture. His acid-fast bacilli smear and culture test results were positive for drug-susceptible M. Tuberculosis through November 2006 because of poor compliance. He was detained for directly observed therapy in December 2006. His acid-fast bacilli smear and culture test results were negative within 1 month. After 7 weeks of receving a supervised dose of isoniazid 300 mg QD, rifabutin 300 mg QD, ethambutol 1200 mg QD, and pyrazinamide 2000 mg QD, supervised HAART was begun with 400 mg of lopinavir/ritonavir 400/100 + tenofovir/emtricitabine QD. Rifabutin, reduced to 150 mg thrice weekly, was given with 300 mg of isoniazid QD to complete 9 months of treatment. A daily dose of pyrazinamide was stopped after 3 months. The patient’s CD4 cell count increased to 134 cells/mm3. He took no medications after he was released from detention. Four months later, he presented to the with cough, weight loss, and a normal chest radiograph. Sputum samples were requested for acid-fast bacilli smear and culture, which yielded rifampin-resistant M. Tuberculosis. Molecular characterization confirmed that the original and relapse isolates were identical. No therapeutic drug monitoring data were available.

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.
Case 3: A third HIV-infected patient with rifampin-resistant M. Tuberculosis infection and a treatment history similar to those of the other 2 patients was reported in April 2008. The patient, a 43-year-old man, previously received a diagnosis of disseminated drug-susceptible M. Tuberculosis infection in April 2007 with a CD4 cell count of 51 cells/mm3. Sputum samples tested negative for M. Tuberculosis on culture after treatment with isoniazid 300 mg QD, rifampin 600 mg QD, pyrazinamide 1500 mg QD, and ethambutol 800 mg QD. The patient was transferred to a nursing facility. Daily doses of isoniazid, rifampin, and pyrazinamide were given until August 2007. Then doses of atazanavir/ritonavir 300/100 + tenofovir/emtricitabine were begun, and rifabutin 150 mg thrice weekly. He took rifabutin 150 mg thrice weekly and daily isoniazid 300 mg QD until November 2007 and then left the nursing facility. In April 2008, with a CD4 cell count of 26 cells/mm3, he presented with a psoas muscle abscess. A sputum sample and a biopsy sample from the psoas muscle yielded rifampin-resistant M. Tuberculosis on culture. Molecular characterization confirmed that the original and relapse isolates were identical. No follow-up therapeutic drug monitoring data were available.

Reference
  • 504
    Agarwala S, Mummaneni V, Randal D, et al. Pharmacokinetic (PK) effect of rifabutin (RIF) on atazanavir (ATV) with and without ritonavir (RTV) in healthy subjects. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, February 2002. Abstract 445-W
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    Atazanavir (Reyataz), Bristol-Myers Squibb, Quebec, Canada, 23 nov. 2017.
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    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.
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    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.
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  • 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.
  • 3151
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