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 nelf inavir and its active M8 metabolite in eight HIV-seropositive patients with liver disease, and to examine the relationship between CYP2C19 activity (g enotype and plasma M8/ nelfinavir metabolic ratio) and the severity of live r disease in these patients. Methods Nelfinavir was given as a single dose (500 or 750 mg) to patients b t beginning therapy and twice (500, 750 or 1000 mg) or three times (250 or 750 mg) daily during chronic therapy. Single-dose pharmacokinetic values we re used to predict multiple-dose regimens. Peak and total plasma exposures between 2-4 mu g ml(-1) and 45-75 mu g ml(-1) h, respectively, and predose levels >0.7 mu g ml(-1) were targeted for multidose nelfinavir. Genotype wa s determined by analysis for CYP2C19*1, CYP2C19*2, and CYP2C19*3. Individua ls 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 classificati on for severity of liver disease. Results Nelfinavir pharmacokinetics were characterized by wide interindivid ual variability, low clearance (181-496 ml min(-1) 70 kg(-1), n=7), and pro longed 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 singl e to multiple dosing. CYP2C19 activity was low (metabolic AUC ratio <0.1) i n four patients with moderate to severe liver disease even though they were genetically extensive CYP2C19 metabolizers (*1/*1 or *1/*2). Three patient s 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 disea se resulted in decreased M8 formation. Long-term HIV suppression is possibl e using low nelfinavir doses in patients with liver disease.