Pharmacokinetics and Dose-Finding of Fragmin in Pediatric Patients at Risk for Thromboembolic Events.
Notice bibliographique
Résumé
Abstract BACKGROUND: Low-molecular-weight heparins are increasingly being used for prophylaxis of thromboembolic events (TE) in children. Fragmin offers the advantage of once-daily dosing. However appropriate dosing and pharmacokinetics (PK) of Fragmin in children are unknown. The objective of the study was to determine once daily dose of Fragmin required in children to achieve anti-Xa levels of 0.10–0.40 Anti-Xa U/mL. PK of Fragmin over all age groups. STUDY DESIGN: Prospective cohort study in non-selected children at increased risk for TE who were being treated at Stollery Children’s Hospital, Edmonton or Hospital for Sick Children, Toronto, Canada. All children received a starting dose of 100 mg/kg, an Anti-Xa level was drawn 4 hours post and dosages were adjusted until the target 0.1–0.4 μ/ml was reached. Children then entered the pharmacokinetic phase and blood was drawn at specified timepoints over several different days for Anti-Xa levels. A sparse sampling scheme and population-based, nonlinear mixed effect model approach were used to assess exposure targets. The primary outcomes were: dose required to achieve therapeutic anti-Xa levels in each of the age groups. observed maximum plasma activity (Cmax), time that Cmax was observed (Tmax), half-life (t1/2) and extravascular plasma clearance (Cl/F). Safety was assessed by collection of data on bleeding and thrombotic events. RESULTS: 43 children were enrolled, 1 developed a TE prior to receiving Fragmin 42 received drug. Two patients developed TE after one dose, 5 withdrew voluntarily and 1 had CVL removed early. 34 received the drug, 31 contributed PK data. A once compartment model with allometrically-scaled clearance and volume best explained observed concentration-time profiles. The median maintenance dose in children under 5 yrs of age was 100 IU/Kg whereas 5–10 and 10–16 yr old required 88 and 63 IU/Kg respectfully. The PK parameters are summarised in Table I. In terms of safety, there were no major bleeding events reported. Minor bleeds were reported in 4 patients: 3 bleeding at insuflon site and 1 oozing from PICC line. Two patients had asymptomatic thrombosis discovered on chance finding: 1 patient with a portal vein thrombosis discovered on routine renal ultrasound which did not resolve on treatment. One patient had a small clot at tip of CVL discovered on routine echocardiogram which did resolve on treatment. CONCLUSIONS: Dosing of Fragmin is age-dependent. The PK studies showed an increase in clearance of Fragmin in younger children. The volume of distribution is approximately equal to plasma volume and remains constant across the studied age ranges. The shift in time to maximum Anti-Xa level maybe due to absorption-related differences which means the 4-hour sampling paradigm is not adequate to judge therapeutic exposure across age groups. Table I: Pharmacokinetic parameters 0−2 months (n=6) 2–12 Months (n=8) 1−5 Years (n=6) 5−10 years (n=4) 10–16 years (n=7) Cmax [IU/mL] 0.13 0.26 0.26 0.29 0.34 Tmax [hours] 1.6 1.8 2.1 2.3 2.6 T1.2 [hours] 0.50 0.61 0.77 0.90 1.08 CL/F [L/hour/kg] 0.046 0.032 0.031 0.024 0.019
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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) | 0,000 | 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 tête enseignante, 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 ».