Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus-infected patients with chronic liver disease.

AIMS: To evaluate the single-dose and multiple-dose pharmacokinetics of nelfinavir and its active M8 metabolite in eight HIV-seropositive patients with liver disease, and to examine the relationship between CYP2C19 activity (genotype and plasma M8/nelfinavir metabolic ratio) and the severity of liver disease in these patients. METHODS: Nelfinavir was given as a single dose (500 or 750 mg) to patients beginning therapy and twice (500, 750 or 1000 mg) or three times (250 or 750 mg) daily during chronic therapy. Single-dose pharmacokinetic values were used to predict multiple-dose regimens. Peak and total plasma exposures between 2-4 microg ml-1 and 45-75 microg ml-1 h, respectively, and predose levels > 0.7 microg ml-1 were targeted for multidose nelfinavir. Genotype was determined by analysis for CYP2C19*1, CYP2C19*2, and CYP2C19*3. Individuals were grouped according to their genotype, molar M8/nelfinavir AUC ratio (low: < 0.1, intermediate: 0.1-0.3, high > 0.3), and Child-Pugh classification for severity of liver disease. RESULTS: Nelfinavir pharmacokinetics were characterized by wide interindividual variability, low clearance (181-496 ml min-1 70 kg-1, n = 7), and prolonged half-life (5-20 h, n = 7). M8/nelfinavir AUC ratio increased 58% (n = 4) and alpha 1-acid glycoprotein levels decreased up to 39% (n = 5) from single to multiple dosing. CYP2C19 activity was low (metabolic AUC ratio < 0.1) in four patients with moderate to severe liver disease even though they were genetically extensive CYP2C19 metabolizers (*1/*1 or *1/*2). Three patients required lower daily doses than the standard regimen of 750 mg every 8 h to achieve target concentrations and maintain virologic suppression at < 50 RNA copies ml-1 (up to 20 months). CONCLUSIONS: Acquired CYP2C19 deficiency from moderate or severe liver disease resulted in decreased M8 formation. Long-term HIV suppression is possible using low nelfinavir doses in patients with liver disease.

"I won't do surgery if you don't try to do my job," head of new blood agency tells MDs. Interview by Anne Mullens.

Ken Fyke is known as a tough administrator, and he is going to need all of his administrative tricks as first chair of Canadian Blood Services, the new national organization that is taking over responsibility for the nation's blood supply from the Red Cross come September. Fyke says he hopes to work closely with physicians, but they will have to realize where their responsibilities end and his begin.

Impact of Mycobacterium avium complex prophylaxis on the incidence of mycobacterial infections and transfusion-requiring anemia in an HIV-positive population.

Disseminated Mycobacterium avium complex (MAC) infection is common in persons with advanced HIV infection and can be prevented by prophylactic use of rifabutin; however, routine prophylaxis is costly and incompletely effective. Chronic anemia is a common manifestation of MAC infection. We conducted a retrospective population study of the annual incidence of MAC bacteremia and blood transfusion for anemia in a regional HIV-positive population before and after the introduction of rifabutin to determine the effect of MAC prophylaxis on the incidence of transfusion-requiring anemia. The HIV-infected patient populations in 1992 and 1993 were comparable in number, severity of immunodeficiency, and zidovudine (ZDV) use. The use of rifabutin for MAC prophylaxis for those with CD4 T-lymphocyte counts < 100/microl increased from 17.2% in 1992 to 33.7% in 1993 (p < 0.001), whereas diagnostic surveillance for MAC bacteremia was stable. In 1993, there was a decrease in the number of HIV-infected persons from whom MAC was isolated (10 vs. 26, p = 0.004), and a significant decrease in the number of patients transfused for anemia (15 vs. 35, p = 0.002), number of transfusion episodes, and numbers of units transfused, associated with significant cost and resource savings. Adoption of MAC prophylaxis was followed by a significant decrease in the number of diagnosed MAC infections and in transfusion requirements in an HIV-positive population with sustained surveillance and similar levels of immunodeficiency, which may represent a health and economic benefit of effective [correction of defective] MAC prophylaxis in a population at risk.