Species Differences in Troxacitabine Pharmacokinetics and Pharmacodynamics
Bibliographic record
Abstract
PURPOSE: Troxacitabine is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models. EXPERIMENTAL DESIGN: Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of [14C]troxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules. RESULTS: Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring >24 hours exposure for maximum activity. Analysis of the intracellular metabolites of [14C]troxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 micromol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity [treated versus control (T/C) of 27% and tumor regression during treatment]. CONCLUSIONS: These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".