12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
12.2 Pharmacodynamics
The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosing period.
12.3 Pharmacokinetics
The pharmacokinetic parameters of XYNTHA in 30 PTPs 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA are summarized in Table 3.
In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow-up pharmacokinetic study. The parameters were comparable between baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA.
In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic parameters in these subjects are also summarized in Table 3.
| Parameter | Initial Visit (n = 30) | Month 6 (n = 25) | Pre-surgery (n=8) |
|---|---|---|---|
| Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state. | |||
| |||
| Cmax (IU/mL) | 1.08 ± 0.22 | 1.24 ± 0.42 | 1.08 ± 0.24 |
| AUC∞ (IU∙hr/mL) | 13.5 ± 5.6 | 15.0 ± 7.5 | 16.0 ± 5.2 |
| t1/2 (hr) | 11.2 ± 5.0 | 11.8 ± 6.2* | 16.7 ± 5.4 |
| CL (mL/hr/kg) | 4.51 ± 2.23 | 4.04 ± 1.87 | 3.48 ± 1.25 |
| Vss (mL/kg) | 66.1 ± 33.0 | 67.4 ± 32.6 | 69.0 ± 20.1 |
| Recovery (IU/dL per IU/kg) | 2.15 ± 0.44 | 2.47 ± 0.84 | 2.17 ± 0.47 |
Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years of age, who are also included in the summary for the adults above, along with five children aged 3.7–5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) is approximately 40% higher in children.
| Parameter | Young Children (n=5) | Adolescents (n=4) |
|---|---|---|
| Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state. | ||
| Age (min - max, yr)) | 3.7 – 5.8 | 14 – 15 |
| Cmax (IU/mL) | 0.78 ± 0.34 | 0.97 ± 0.21 |
| AUC∞ (IU∙hr/mL) | 12.2 ± 6.50 | 8.5 ± 4.0 |
| t1/2 (hr) | 8.3 ± 2.7 | 6.9 ± 2.4 |
| CL (mL/hr/kg) | 6.29 ± 4.87 | 6.62 ± 2.16 |
| Vss (mL/kg) | 66.9 ± 55.6 | 67.1 ± 13.6 |
| Recovery (IU/dL per IU/kg) | 1.52 ± 0.69 | 1.95 ± 0.41 |