Assessment of Individual Characteristics on the Pharmacokinetics of Oral Busulfan in Adults Patients Undergoing Hematopoietic Stem-Cell Transplantation.
Notice bibliographique
Résumé
Abstract Introduction Busulfan is one of the most commonly used drugs in preparative regimens for hematopoietic stem-cell transplantation. Administration of accurate doses of busulfan is critical to limit toxicity while ensuring maximum efficacy. Indeed, busulfan pharmacokinetics exhibit important interpatient variability and its therapeutic interval is narrow. Objective To determine the impact of glutathione-S-transferase (GST) genotype and individual characteristics on the pharmacokinetics of oral busulfan in adult patients. Methods An observational retrospective study was performed. Individual characteristics were obtained from the medical charts of adult patients who received oral busulfan between June 2003 and May 2007. Genotype for the enzyme GST A1 was determined in patients for whom consent was available. Linear regression analysis was used to identify the variables that have significant impact on oral clearance of the first dose of busulfan. Oral and intravenous pharmacokinetics were also compared in patients presenting between November 2006 and May 2007. Results Oral clearance on the first dose of busulfan was available for 104 of the 106 eligible patients. Lean body weight (LBW) was used to determine the dose and was a significant predictor of oral clearance (r = 0,61; r2 = 0,37). No added precision was obtained with the addition of age, bilirubin and hepatic transaminase levels (r = 0,62; r2 = 0,38). GST genotype was determined for 87 patients and an increase in precision is obtained when adding GST genotype to LBW for prediction of oral clearance (r = 0,65; r2 = 0,43). The impact of GST genotype was found to be independent of all other variables considered. The model that includes LBW, GST genotype, age, bilirubin and hepatic transaminase levels provides little further precision (r = 0,67; r2 = 0,45). No significant impact was identified when considering the following variables: gender, creatinine clearance, albumin, lactate deshydrogenase and alkaline phosphatase levels, prior history of chemotherapy and/or radiotherapy, concomitant use of acetaminophen or antifungal drugs. The impact of GST genotype (*A wild-type allele, *B variant allele with reduced activity) on oral clearance was also evaluated. A significant difference in busulfan clearance between individuals with the *A/*A genotype and individuals with the *B/*B genotype was observed (p = 0,003; ANOVA and Bonferroni). In the prospective study, eight patients agreed to receive their second dose of busulfan via the intravenous route. Oral clearance was a good estimation of absolute clearance (Student’s t-test for mean difference p = 0,573; r = 0,963). Volume of distribution of busulfan was an excellent predictor of oral clearance for the 8 patients (r = 0,96; r2 = 0,93) and LBW was an adequate predictor of volume of distribution (r = 0,94; r2 = 0,88). Conclusion An increase in precision could be obtained by adjusting the busulfan dose with LBW and GST genotype rather than LBW alone. No other individual patient characteristic was identified that influences significantly the pharmacokinetics of oral busulfan. More than 50% of intersubject variability in busulfan oral pharmacokinetics remains unexplained even after considering all above variables. Estimation of volume of distribution may represent a very innovative and promising avenue to more closely predict busulfan dosage.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».