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Xyntha

Clinical Pharmacology
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CLINICAL PHARMACOLOGY

Xyntha

Mechanism of Action

Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia).15 Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X.15 Activated factor X converts prothrombin into thrombin.15 Thrombin then converts fibrinogen into fibrin, and a clot is formed.15 Factor VIII activity is greatly reduced in patients with hemophilia A, and, therefore, replacement therapy is necessary. The administration of XYNTHA increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in these patients.

Pharmacodynamics

The administration of XYNTHA increases plasma levels of factor VIII activity and can temporarily correct the coagulation defect in hemophilia A patients.

Pharmacokinetics

In a pivotal crossover clinical study, 30 evaluable previously treated patients [PTP] ( ≥ 12 years) received a single infusion of 50 IU/kg of XYNTHA followed by a full-length recombinant FVIII (FLrFVIII, Advate®) or a single infusion of FLrFVIII followed by XYNTHA in a randomized crossover design. The one-stage clotting assay method was used to determine the concentrations of these two products in blood. XYNTHA was shown to be pharmacokinetically equivalent to FLrFVIII as the 90% confidence intervals for XYNTHA-to-FLrFVIII ratios of the mean values of Cmax and AUC∞ were within pre-established limits of 80% to 125%. The pharmacokinetic parameters of XYNTHA in the above group of patients are summarized in Table 2.

In addition, 25 PTPs received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow up PK study. The pharmacokinetic parameters were comparable between baseline and month 6 indicating no time-dependent changes in the pharmacokinetic properties of XYNTHA; the 90% confidence intervals for XYNTHA 6 month-to-baseline ratios of the mean values of Cmax and AUC∞ were within pre-established limits of 80% to 125%.

Table 2: Pharmacokinetic Parameter Estimates for XYNTHA at Baseline (Cross-over phase) and Month 6 (Follow-up phase) in Previously Treated Patients with Hemophilia A

Parameter Parameters at Initial Visit
(Crossover phase, n = 30)
Mean ± SD		 Parameters at Month 6
(Follow-up phase, n = 25)
Mean ± SD
Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42
AUC∞ (IU·hr/mL) 13.5 ± 5.6 15.0 ± 7.5
t1/2 (hr) 11.2 ± 5.0 11.8 ± 6.2*
CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87
K-value    
(IU/dL per IU/kg) In vivo Recovery (%) 2.15 0.44 103 ± 21 2.47 0.84 116 ± 40
Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; K-value = incremental recovery; t1/2 = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation.
* One subject was excluded from the calculation due to lack of a well-defined terminal phase.

Animal Toxicology and/or Pharmacology

Brand Name: Xyntha
Generic Name: Antihemophilic Factor
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