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

Yasmin Khaliq, Keith Gallicano, Isabelle Seguin, Kathryn Fyke, Germain Carignan, Dennis Bulman, Andrew David Badley, D. William Cameron

Research output: Contribution to journalArticle

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Abstract

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 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. 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 α1-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.

Original languageEnglish (US)
Pages (from-to)108-115
Number of pages8
JournalBritish Journal of Clinical Pharmacology
Volume50
Issue number2
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Nelfinavir
Liver Diseases
Chronic Disease
Pharmacokinetics
HIV
Area Under Curve
Genotype
Cytochrome P-450 CYP2C19
Half-Life
Glycoproteins
RNA
Acids
Therapeutics

Keywords

  • CYP2C19
  • Liver disease
  • Nelfinavir
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus-infected patients with chronic liver disease. / Khaliq, Yasmin; Gallicano, Keith; Seguin, Isabelle; Fyke, Kathryn; Carignan, Germain; Bulman, Dennis; Badley, Andrew David; Cameron, D. William.

In: British Journal of Clinical Pharmacology, Vol. 50, No. 2, 2000, p. 108-115.

Research output: Contribution to journalArticle

Khaliq, Yasmin ; Gallicano, Keith ; Seguin, Isabelle ; Fyke, Kathryn ; Carignan, Germain ; Bulman, Dennis ; Badley, Andrew David ; Cameron, D. William. / Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus-infected patients with chronic liver disease. In: British Journal of Clinical Pharmacology. 2000 ; Vol. 50, No. 2. pp. 108-115.
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abstract = "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 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. 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 α1-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.",
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T1 - Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus-infected patients with chronic liver disease

AU - Khaliq, Yasmin

AU - Gallicano, Keith

AU - Seguin, Isabelle

AU - Fyke, Kathryn

AU - Carignan, Germain

AU - Bulman, Dennis

AU - Badley, Andrew David

AU - Cameron, D. William

PY - 2000

Y1 - 2000

N2 - 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 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. 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 α1-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.

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KW - CYP2C19

KW - Liver disease

KW - Nelfinavir

KW - Pharmacokinetics

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