Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India.
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Study Design
A randomized, multiple-dose, parallel-group study by Zhang, et al1, was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily. Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modeling and simulation techniques were utilized, integrating data across several healthy subject studies.
In the Ramachandran study, sixteen adult HIV-infected patients with tuberculosis were included. These patients were being treated with an atazanavir/ritonavir-containing ART regimen and a short-course thrice-weekly anti-tuberculosis regimen containing rifabutin (RBT) 150mg thrice-weekly. Serial blood draws at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 hours after drug administration were done. Plasma RBT was estimated by HPLC. The target peak concentration range was taken as 0.3 – 0.8 µg/ml.
Study Results
In the Zhang study, the pharmacokinetic parameters (Cmax, AUC24avg and Cmin) 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.
In the Ramachandran study, Peak RBT concentrations were below the lower limit of therapeutic range in seven patients, while there were no patients with peak concentrations above the upper therapeutic limit. Taking 0.06µg/ml as the minimal inhibitory concentration (MIC) of RBT against M. tuberculosis, 10 patients had their trough concentration < MIC, trough levels being undetectable in five patients. Significant correlations were observed between CD4 cell counts and peak concentration (p=0.044), trough concentration (p=0.002) and exposure (p=0.028). Multiple regression analysis showed sex and CD4 cell counts to significantly influence RBT peak concentrations, the p values being 0.008 and 0.024 respectively.
Study Conclusions
With the concomitant use of rifabutin and atazanavir, it is recommended to reduce the dosage of rifabutin by 75% (150mg every other day or three times a week) due to increased rifabutin concentrations.
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 in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability. However, sub-therapeutic RBT peak concentrations and trough concentrations below the MIC in a high proportion of HIV positive patients is a matter of concern, and suggestive of inadequate dosing2. Prospective studies in different settings are required to arrive at the proper therapeutic dose of RBT to be used during RTV coadministration, in order to achieve therapeutic success.
References
Ramachandran G, Bhavani PK, Hemanth Kumar AK, Srinivasan R, Raja K, Sudha V, Swaminathan S. Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in hiv-infected tb patients in india. International Journal Of Tuberculosis And Lung Disease. 2013; 12: 1564-1568.
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