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XYNTHA® Solofuse Lyophilized Powder for Solution in Prefilled Dual-chamber Syringe (antihemophilic factor [Recombinant]) Clinical Pharmacology

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.

Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose
ParameterInitial 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.
*
One subject was excluded from the calculation due to lack of a well-defined terminal phase.
Cmax (IU/mL)1.08 ± 0.221.24 ± 0.421.08 ± 0.24
AUC
(IU∙hr/mL)
13.5 ± 5.615.0 ± 7.516.0 ± 5.2
t1/2 (hr)11.2 ± 5.011.8 ± 6.2*16.7 ± 5.4
CL (mL/hr/kg)4.51 ± 2.234.04 ± 1.873.48 ± 1.25
Vss (mL/kg)66.1 ± 33.067.4 ± 32.669.0 ± 20.1
Recovery
(IU/dL per IU/kg)
2.15 ± 0.442.47 ± 0.842.17 ± 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.

Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose
ParameterYoung 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 – 5.814 – 15
Cmax (IU/mL)0.78 ± 0.340.97 ± 0.21
AUC (IU∙hr/mL)12.2 ± 6.508.5 ± 4.0
t1/2 (hr)8.3 ± 2.76.9 ± 2.4
CL (mL/hr/kg)6.29 ± 4.876.62 ± 2.16
Vss (mL/kg)66.9 ± 55.667.1 ± 13.6
Recovery
(IU/dL per IU/kg)
1.52 ± 0.691.95 ± 0.41

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