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Lower Doses of Mycobutin (Rifabutin), Every Other Day, May Offer as Much Protection as Standard Doses in Advanced HIV: Presented at ICAAC

By Paula Moyer

WASHINGTON, DC -- December 23, 2005 -- Patients with advanced HIV who receive prophylactic rifabutin (Mycobutin) along with highly active antiretroviral therapy (HAART) get as much benefit from treatment every other day as from daily treatment, researchers reported here at the 45^th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

"The reduced dose and the every-other-day frequency was well tolerated in this study," reported principal investigator Ya-Chi Chen, PharmD, clinical pharmacologist, clinical pharmacology and discovery medicine department, GlaxoSmithKline, Research Triangle Park, North Carolina. She is now a researcher with Daiichi Asubio Pharmaceuticals.

"This regimen is recommended when co-administered with the antiretroviral drugs used in this research," she added in her presentation on December 17^th.

The investigators studied the dosing issue of rifabutin with fosamprenavir (Lexiva, Telzir), boosted with ritonavir (Norvir). Fosamprenavir is the phosphate ester prodrug of amprenavir. Rifabutin is an antimycobacterial agent used to treat tuberculosis and prevent Mycobacterium avium complex in HIV-infected patients.

The investigators wanted to assess the steady-state interaction between fosamprenavir/ritonavir and a reduced dose of rifabutin. Rifabutin is usually given on a daily basis.

The investigators conducted a phase 1, randomized, open-label, balanced, crossover drug interaction study in 35 healthy adult subjects. The subjects first received rifabutin daily at a dose of 300 mg for 14 days and then 150 mg every other day for 14 days. In the second study period, they also received 700 mg of fosamprenavir and 100 mg of ritonavir twice daily. A washout period of 21 to 28 days occurred between the 2 treatment periods.

Plasma levels of amprenavir, rifabutin, and 25-O-desacetylrifabutin, a metabolite of rifabutin, were measured, and the pharmacokinetic parameters and geometric least squares (GLS) mean ratios were calculated in order to compare plasma rifabutin and 25-O-desacetylrifabutin pharmacokinetic parameters following fosamprenavir and ritonavir plus rifabutin against those following rifabutin alone.

Of the original subjects, 17 completed both treatments.

GLS mean ratios for rifabutin area-under-the curve (AUC) and maximum concentration were 0.95 and 0.86, respectively. For 25-O-desacetylrifabutin the AUC was < 10% that of the parent following the treatment period with 300 mg of rifabutin daily. The GLS mean ratios for 25-O-desacetylrifabutin AUC and maximum concentration were 10.2 and 5.8, respectively.

The investigators concluded that rifabutin exposure following the lower dose administered every other day was similar to exposure following the standard dose administered daily.

Consistent with other protease inhibitors, fosamprenavir and ritonavir markedly increased 25-O-desacetylrifabutin.

The investigators concluded that 150 mg of rifabutin every other day is an appropriate dose and schedule when patients are also receiving fosamprenavir and ritonavir at the doses used in this study.

Norvir is manufactured by Abbott Laboratories, Lexiva and Telzir are manufactured by GlaxoSmithKline, and Mycobutin is manufactured by Pharmacia. GlaxoSmithKline funded the study.


[Presentation title: Pharmacokinetic Interaction Between Rifabutin (RFB) and Fosamprenavir (FPV)/Ritonavir (RTV) in Healthy Subjects. Abstract A-1199]

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