OBJECTIVES: Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir. PATIENTS AND METHODS: A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776. RESULTS: The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co-administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infected patients. CONCLUSIONS: The benefits to HIV/TB co-infected patients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability.
RCT Entities:
OBJECTIVES: Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir. PATIENTS AND METHODS: A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776. RESULTS: The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co-administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infectedpatients. CONCLUSIONS: The benefits to HIV/TB co-infectedpatients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability.
Authors: Michelle A Kendall; Umesh Lalloo; Courtney V Fletcher; Xingye Wu; Anthony T Podany; Sandra W Cardoso; Prudence Ive; Constance A Benson Journal: Clin Infect Dis Date: 2021-08-16 Impact factor: 20.999
Authors: Amanda M Healan; J McLeod Griffiss; Howard M Proskin; Mary Ann O'Riordan; Wesley A Gray; Robert A Salata; Jeffrey L Blumer Journal: Antimicrob Agents Chemother Date: 2017-12-21 Impact factor: 5.191
Authors: Stefanie Hennig; Elin M Svensson; Ronald Niebecker; P Bernard Fourie; Marc H Weiner; Stefano Bonora; Charles A Peloquin; Keith Gallicano; Charles Flexner; Alex Pym; Peter Vis; Piero L Olliaro; Helen McIlleron; Mats O Karlsson Journal: J Antimicrob Chemother Date: 2016-01-31 Impact factor: 5.790