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Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus‐infected patients with chronic liver disease
Author(s) -
Khaliq Yasmin,
Gallicano Keith,
Seguin Isabelle,
Fyke Kathryn,
Carignan Germain,
Bulman Dennis,
Badley Andrew,
Cameron D. William
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00238.x
Subject(s) - nelfinavir , pharmacokinetics , medicine , pharmacology , cyp2c19 , liver disease , gastroenterology , dosing , viral load , virology , human immunodeficiency virus (hiv) , antiretroviral therapy , metabolism , cytochrome p450
AimsTo 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.MethodsNelfinavir 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 µg ml −1 and 45–75 µg ml −1 h, respectively, and predose levels > 0.7 µg 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.ResultsNelfinavir 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 α 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).ConclusionsAcquired 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.