Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus
Bibliographic record
Abstract
AIM: Our aim was to evaluate the effect of ketoconazole on ritonavir and saquinavir plasma and cerebrospinal fluid (CSF) concentrations. METHODS: Twelve patients who were human immunodeficiency virus-seropositive and who were receiving 400 mg of ritonavir and 400 mg of saquinavir twice daily completed a nonfasted, two-period, two-group, longitudinal pharmacokinetic study. Blood samples were collected over the daytime 12-hour dosing interval of the protease inhibitors at baseline (period 1, day 0) and after 10 days of coadministration of 200 mg (n = 6) or 400 mg (n = 6) of ketoconazole once daily (period 2, day 10). One set of paired CSF and blood samples was collected between 4 and 5 hours after the dose on both days. RESULTS: Ketoconazole significantly increased area under the plasma concentration-time curve, plasma concentration at 12 hours after the dose, and half-life of ritonavir by 29% (95% confidence interval (CI), 13%-46%), 62% (95% CI, 37%-92%), and 31% (95% CI, 13%-51%), respectively. Similar increases of 37% (95% CI, 4%-81%), 94% (95% CI, 41%-167%), and 38% (95% CI, 15%-66%), respectively, were observed for these parameters for saquinavir. Ketoconazole significantly elevated ritonavir CSF concentration by 178% (95% CI, 59%-385%), from 2.4 to 6.6 ng/mL, with no change in paired unbound plasma level (26 ng/mL); this led to a commensurate 181% increase (95% CI, 47%-437%) in CSF/plasma unbound ratio. All pharmacokinetic changes were unrelated to ketoconazole dose or plasma exposures. Corresponding changes for saquinavir CSF pharmacokinetics were insignificant (P > .06); saquinavir CSF levels were unmeasurable in 7 patients (<0.2 ng/mL). CONCLUSIONS: The disproportionate increase in CSF compared with plasma concentrations of ritonavir is consistent with ketoconazole inhibiting both drug efflux from CSF and systemic clearance.
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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".