Quality of Evidence: High
Coadministration of lopinavir/ritonavir and rifabutin had no clinically significant effect on lopinavir exposure, whereas initial pharmacokinetic studies in healthy volunteers showed a significant increase in rifabutin and its active metabolite (25-O-desacetyl rifabutin) concentrations. Thus, a reduction of rifabutin dosage to 150 mg three times a week was recommended to reduce the risk of rifabutin related toxicity. However, more recent pharmacokinetic data derived from HIV/TB co-infected patients have shown that the coadministration of lopinavir/ritonavir (400/100 mg twice daily) and rifabutin (150 mg 3 times a week) resulted in rifabutin concentrations that were lower than those observed with rifabutin 300 mg once daily without protease inhibitors suggesting that rifabutin dosage may be inadequate. Of interest, cases of relapses with acquired rifamycin-resistant Mycobacterium tuberculosis infection have been described in co-infected patients treated with rifabutin 150 mg 3 times a week and lopinavir/ritonavir or atazanavir/ritonavir. The US guidelines for HIV treatment now recommend the administration of rifabutin at a daily dosage of 150 mg with a boosted protease inhibitor. Due to the limited safety data with this dose and combination, patients receiving rifabutin 150 mg daily with a boosted protease inhibitor should be closely monitored for rifabutin-related toxicities (i.e. uveitis or neutropenia).
When rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent drug and active 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5- and 5.7-fold, respectively. When given with Kaletra the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommended for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for Kaletra.
Kaletra Summary of Product Characteristics, AbbVie Ltd, January 2021.
Coadministration of rifabutin (150 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) to 14 HIV- subjects resulted in increases in lopinavir Cmax, AUC and Cmin of 8%, 17% and 20% respectively. Data in 12 subjects, and compared to rifabutin 300 mg once daily alone, showed increases in rifabutin Cmax, AUC and Cmin of 2.1-, 3.0- and 4.9-fold. Cmax, AUC and Cmin for 25-O-desacetyl rifabutin increased by 23.6-, 47.5- and 94.9-fold. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Kaletra Prescribing Information, AbbVie Ltd, October 2020.
Patients with TB-HIV co-infection (n=16) received rifabutin (300 mg once daily) in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and lopinavir/ritonavir based ART with rifabutin (150 mg three times weekly or 150 mg daily). The rifabutin dose with ART was switched after 1 month. Rifabutin AUC and Cmax in patients taking 150 mg rifabutin three times weekly was significantly reduced compared to the other treatment arms: AUC and Cmax decreased by 40% and 50% when compared to 300 mg once daily, and decreased by 60% and 50% when compared to 150 mg daily. 86% of patients on the three times weekly rifabutin arm had an AUC < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance. Plasma d-RBT concentrations increased 5-fold with three times weekly rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. A daily 150 mg dose of rifabutin in combination with lopinavir/ritonavir safely maintained rifabutin plasma concentrations in line with those shown to prevent resistance.
Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam. Naiker S, Connolly C, Wiesner L, et al. BMC Pharmacol Toxicol, 2014, 15:61.
A randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis evaluated rifabutin pharmacokinetics before and after the introduction of lopinavir/ritonavir. Rifabutin and 25-O-desacetyl rifabutin concentrations were measured after 2 weeks of rifabutin 300 mg daily alone, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir (n=12) and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir (n=13). Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2-5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.
Plasma concentrations of rifabutin and 25-O-desacetyl rifabutin were determined in 16 HIV/TB coinfected patients who were receiving rifabutin 300 mg/day (n=9) rifabutin or 150 mg every other day (n=7) in combination with lopinavir/ritonavir. The mean Cmax and AUC of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than in those on 300 mg/day, while the mean Cmax and AUC of 25-O-desacetyl rifabutin were 186% and 152% higher, respectively. Total concentrations of rifabutin+metabolite were similar between the groups within the first 24 hours, but remained low during the subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing.
Pharmacokinetics of rifabutin in Japanese HIV-infected patients with or without antiretroviral therapy. Tanuma J, Sano K, Teruya K, et al. PLoS One, 2013, 8(8): e70611.
The pharmacokinetics of rifabutin before and after the addition of lopinavir/ritonavir were examined in 10 patients with HIV infection and active tuberculosis. Samples were collected 2-4 weeks after starting rifabutin (300 mg thrice weekly) without lopinavir/ritonavir, 2 weeks after the addition of lopinavir/ritonavir (400/100 mg twice daily) to rifabutin(150 mg thrice weekly), and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir/ritonavir. Concentrations of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir were determined. Low rifabutin Cmax values were observed in 5/10 patients on rifabutin 300 mg without lopinavir/ritonavir. After the addition of lopinavir/ritonavir to rifabutin 150 mg, 9/10 had low Cmax values. Eight patients had dose increases to 300 mg rifabutin with lopinavir/ritonavir. Most free rifabutin (unbound to plasma protein) Cmax values were below the tuberculosis minimal inhibitory concentration. For most patients, values for AUC were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance. One of the 10 patients experienced relapse with acquired rifamycin resistance. The recommended rifabutin doses for use with lopinavir/ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.
Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis. Boulanger C, Hollender E, Farrell K, et al. Clin Infect Dis, 2009, 49(9): 1305-1311.
Coadministration of rifabutin alone (150 mg once daily) or rifabutin (150 mg three times weekly) plus lopinavir/ritonavir (400/100 mg twice daily) was studied in 14 HIV- subjects. Point estimates for the sum of rifabutin and 25-O-desacetyl rifabutin Cmax and AUC48h were approximately 3-fold higher in the combination phase. Pharmacokinetic sampling that was originally planned for day 12 of the combination phase had to be performed on day 10 when study drugs were discontinued due to rifabutin-associated adverse events (13/14 subjects reported at least one adverse event).
Pharmacokinetics of rifabutin 150 mg TIW plus lopinavir/ritonavir 400/100 mg bid administered in healthy adult subjects. Ng J, Nada A, Freeman S, et al. 10th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, April 2009, abstract O21.
Coadministration of lopinavir/ritonavir (400/100 mg twice daily) and rifabutin (150 mg once daily) was studied in 3 HIV+ patients previously receiving rifabutin alone (300 mg once daily). Following the addition of lopinavir/ritonavir there was wide inter-subject variability in rifabutin pharmacokinetics: AUCs increased in 2 patients (68% and 402%) and decreased in 1 patient (31%); Cmax values for these patients showed a 11% decrease, a 166% increase and a 64% decrease respectively. Lopinavir pharmacokinetics were not significantly affected (compared to historical data).
Pharmacokinetics of rifabutin coadministered with lopinavir/ritonavir in HIV patients affected by tuberculosis. Bonora S, Boffito M, D’Avolio A, et al. 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, July 2003, abstract 863.