Effect of Normal Variation in Factor VIII Pharmacokinetics on Prophylactic Dosing Requirements in Severe Classical Hemophilia.
Notice bibliographique
Résumé
Abstract We have previously shown that break-through bleeding in children with severe hemophilia A on prophylaxis is associated with time/week with FVIII less than 1IU/dL (P<0.0001) (Collins et al. JTH. 2008;O-T-018). In clinical practice many clinicians use the trough FVIII to monitor prophylaxis. These parameters depend on dose and frequency of infused FVIII and the patient’s FVIII recovery and elimination half-life (t½). To help guide prescription of prophylactic regimens in clinical practice we aimed to establish the relative importance of these variables on FVIII levels using results from 48 patients aged 1–6 yrs who had undergone a 48h, 50IU/kg pharmacokinetic (PK) study with Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (Advate). The median (5–95 percentile) recovery was 1.8 (1.4–2.8) IU/dL/IU/kg and t½ 9.4 (7.4–13.1) h. A standard prophylactic regimen (30IU/kg on alternate days) in an average patient (recovery 1.8, t ½ 9.4h) was considered baseline. Each variable was individually adjusted within the observed normal range or clinical practice whilst holding the other variables constant and the effect on trough level and time/week FVIII <1IU/dL was calculated (table). Variable Trough (IU/dL) Time/wk <1IU/dL (h) t½ (hrs) 7.4 <1 17.5 9.4 1.6* 0* 13.1 4.4 0 Recovery 1.4 1.2 0 1.8 1.6* 0* (IU/dL)/(IU/kg) Dose (IU/kg) 2.8 2.5 0 20 1.1 0 30 1.6* 0* 50 2.7 0 Frequency (days) Daily (15 IU/kg) 4.8 0 Alternate day (30 IU/kg) 1.6* 0* Every 3rdday (45 <1 27.8 The in silico modelling showed that the standard regimen in the average patient resulted in a trough level of 1.6IU/dL and no time per week with FVIII <1 (* in table). In contrast, the commonly used regimen of 30IU/kg on Mon/Wed/Fri in the same patient would result in FVIII <1IU/dL for 17.4h on Sunday. The Friday dose would have to be increased to 108.5IU/kg to maintain a trough level above 1IU/dL. Dosing frequency and t½ both had large effects on trough FVIII level and time/week <1IU/dL. Recovery and dose had no effect on time/week with FVIII <1IU/dL and a relatively small effect on trough level. Patients on a standard regimen (30IU/kg alternate day), who have a recovery and t½ on the 5th percentile (1.4IU/dL/IU/kg and 7.4h, respectively), would have a trough level <1IU/dL for approximately 29h per week. In contrast, a patient at the 95th percentile for these parameters (2.8 IU/dL/IU/kg and 13.1h, respectively), would have a trough level of approximately 7IU/dL, spending no time below 1IU/dL. After a 30IU/kg infusion, variation in t½ from 5th to 95th percentile results in a 33h difference from 43 to 76h in time until FVIII falls below 1IU/dL. A similar variation in recovery leads to a 10h difference from 50 to 60h. Increasing the infused dose from 20–50IU/kg in the average patient results in an increase in time until FVIII falls below 1IU/dL of 12h from 50 to 62h. These data confirm that tailoring prophylaxis to bleeding patterns may be enhanced by knowledge of individual patients’ PK. The use of standard 48h PK studies are not practical in clinical practice but techniques are available to estimate individual PK from sparse data that can be obtained in clinical practice. A population PK model under development is one method that will allow individual patient’s PK to be calculated from 3–4 sample points and facilitate the measurement of PK in routine clinical practice. An algorithm based on PK and desired FVIII levels can be used to calculate individualised dosing schedules for patients. In conclusion, to maintain FVIII at a pre-determined level, the frequency of infusion and half life have a more pronounced affect than dose and recovery.
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 | 0,002 | 0,007 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| 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 ».