Pharmacokinetic Evaluation of Rifabutin in Combination with Lopinavir‐Ritonavir in Patients with HIV Infection and Active Tuberculosis

Boulanger, Catherine; Hollender, Elena S.; Farrell, Karen; Stambaugh, Jerry Jean; Maasen, Diane; Ashkin, David; Symes, Stephen; Espinoza, Luis; Rivero, Rafael O.; Graham, Jenny Jo; Peloquin, Charles A.

doi:10.1086/606056

Cited by 91 publications

(67 citation statements)

References 16 publications

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“…As this was an explorative, crossover trial, no formal sample size calculations were performed. However, a minimum of at least 13 volunteers completing all sessions was considered sufficient to allow for relevant conclusions (5,12,17,20,22). With this number of volunteers and the expected within-subject variation on the logarithmic scale of 0.035 in AUC from time point zero up to the time point of the last quantifiable concentration (AUC last ) for DRV, the range of the 90% confidence interval (CI) of the ratio was estimated to be from Ϫ12.3% to ϩ14.0%.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

Sekar¹,

Lavreys²,

Casteele³

et al. 2010

Antimicrob Agents Chemother

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The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC 12h ) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (C min ) increased by 64% and the maximum plasma concentration (C max ) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUC ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n ‫؍‬ 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.The protease inhibitor (PI) darunavir (DRV) with low-dose ritonavir (DRV/r) has demonstrated substantial efficacy and safety across the whole treatment spectrum of HIV-1-infected patients (6,13,14). DRV/r is approved in the United States (25), Europe (26), and other countries for treatment-experienced (600/100 mg twice a day [BID]) and treatment-naïve (800/100 mg once a day [QD]) HIV-1-infected adult patients.Rifabutin (RFB) is an antibiotic used in patients with HIV infection to prevent and treat disseminated Mycobacterium avium complex infections and (in combination with other agents) to treat tuberculosis (16). Patients already receiving DRV/r may, therefore, also need to receive RFB.The predominant metabolite of RFB is 25-O-desacetylrifabutin (desRFB), which is normally present at 10-fold lower plasma concentrations than RFB. DesRFB has similar activity to RFB and contributes up to 10% o...

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

Sekar¹,

Lavreys²,

Casteele³

et al. 2010

Antimicrob Agents Chemother

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“…Subtherapeutic levels of rifabutin have been associated with the development of acquired rifamycin resistance (257). This is illustrated by case reports of the development of TB relapse due to acquired rifampin resistance after treatment with everyother-day rifabutin and ritonavir-boosted PI-based ART (28,134). There remains a critical need to better understand the pharmacokinetic interactions between rifabutin and protease inhibitors in HIV-infected patients.…”

Section: Rifabutin Can Be Used With Protease Inhibitorsmentioning

confidence: 99%

“…There remains a critical need to better understand the pharmacokinetic interactions between rifabutin and protease inhibitors in HIV-infected patients. Rifabutin drug concentration monitoring may be warranted during treatment when it is feasible (28).…”

Section: Rifabutin Can Be Used With Protease Inhibitorsmentioning

confidence: 99%

HIV and Tuberculosis: a Deadly Human Syndemic

2011

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SUMMARY A syndemic is defined as the convergence of two or more diseases that act synergistically to magnify the burden of disease. The intersection and syndemic interaction between the human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had deadly consequences around the world. Without adequate control of the TB-HIV syndemic, the long-term TB elimination target set for 2050 will not be reached. There is an urgent need for additional resources and novel approaches for the diagnosis, treatment, and prevention of both HIV and TB. Moreover, multidisciplinary approaches that consider HIV and TB together, rather than as separate problems and diseases, will be necessary to prevent further worsening of the HIV-TB syndemic. This review examines current knowledge of the state and impact of the HIV-TB syndemic and reviews the epidemiological, clinical, cellular, and molecular interactions between HIV and TB.

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“…A pharmacokinetic study by Boulanger et al measured the drug concentrations of rifabutin and lopinavir-ritonavir as well as the rifabutin metabolite, 25-desacetyl rifabutin, in HIV positive patients with active tuberculosis. (Boulanger et al, 2009) When rifabutin was administered at 150 mg thrice weekly in combination with lopinavir-ritonavir a majority of the patients had C max values below the normal range (0.3 to 0.9 ug/ml). PK-PD simulations by the authors suggested that when the two medications are administered together, rifabutin should be given daily, and that doses as high as 450 mg daily would be needed to achieve free drug plasma concentrations at or above the minimum inhibitory concentration (MIC) for part of the dosing interval.…”

Section: Rifabutin and The Pismentioning

confidence: 98%

Rifamycin Use in HIV-Infected Patients with Tuberculosis

Barth¹,

Egelund²,

Peloquin³

2011

Recent Translational Research in HIV/AIDS

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Pharmacokinetic Evaluation of Rifabutin in Combination with Lopinavir‐Ritonavir in Patients with HIV Infection and Active Tuberculosis

Abstract: The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Cited by 91 publications

References 16 publications

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

HIV and Tuberculosis: a Deadly Human Syndemic

Rifamycin Use in HIV-Infected Patients with Tuberculosis

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