Effect of Normal Variation in Factor VIII Pharmacokinetics on Prophylactic Dosing Requirements in Severe Classical Hemophilia.
Bibliographic record
Abstract
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.
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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 | 0.002 | 0.007 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".