Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus‐infected patients with chronic liver disease
Bibliographic record
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 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".