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.