Abstract
Abstract 1416
A population pharmacokinetic (PK) model of a recombinant FVIII (rFVIII) was established on ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) studies in pediatric and adult patients with hemophilia A. The objective of this analysis was to evaluate the effect of reduced PK sampling time points on the estimated PK parameters in the population PK model.
Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets (11 time points) for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets (5 time points) for 52 children, aged 1 to 6 years. A population PK analysis was conducted on a two-compartment structure model and the covariate effect of age and weight was explored.
Four reduced sampling scenarios from the full 10 post-infusion sampling time points, were investigated: 1) Reduced to 4 (1 hr, 9 hr, 24 hr, and 48 hr), 2) Reduced to 3 (6 hr, 24 hr, and 48 hr), 3) Reduced to 2 (6 hr and 24 hr), and 4) Reduced to 1 sampling time points (24 hr post-infusion). After applying the reduced sampling on a random 10% of sampling set at a time in the population PK model, the differences in model estimates and individual PK estimates between full and reduced sampling, were evaluated.
The two-compartment population PK model adequately described the data. Clearance (CL) was significantly correlated with age and body weight and central volume of distribution was also related with body weight.
Absolute deviations (%) from the estimates using full PK sampling in the Individual PK estimates (CL, Vss, and Half-life) using each of the reduced sampling time points were showed in the below table.
| . | Median Absolute Deviation % from Full Sampling . | |||
|---|---|---|---|---|
| Reduced to 4 . | Reduced to 3 . | Reduced to 2 . | Reduced to 1 . | |
| Clearance [mL/(Kg*hr)] | 2.79 | 3.15 | 3.06 | 5.34 |
| Volume [dL/kg] | 2.23 | 3.88 | 3.94 | 4.20 |
| Half-life [hr] | 2.67 | 3.75 | 4.03 | 4.43 |
| . | Median Absolute Deviation % from Full Sampling . | |||
|---|---|---|---|---|
| Reduced to 4 . | Reduced to 3 . | Reduced to 2 . | Reduced to 1 . | |
| Clearance [mL/(Kg*hr)] | 2.79 | 3.15 | 3.06 | 5.34 |
| Volume [dL/kg] | 2.23 | 3.88 | 3.94 | 4.20 |
| Half-life [hr] | 2.67 | 3.75 | 4.03 | 4.43 |
It appears that PK parameters estimated using population PK model are robust to reduced sampling time points. Accurate measurement of PK on reduced samples gives patients and clinicians the opportunity to design treatment regimens that are better tailored to individuals.
Oh:Baxter: Employment. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fischer:Baxter: Consultancy; NovoNordisk: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Research Support. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter Bioscience: Employment.
Author notes
Asterisk with author names denotes non-ASH members.
