BENEFIX® Clinical Pharmacology

(Coagulation Factor IX (Recombinant))

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

BeneFIX temporarily replaces the missing clotting factor IX that is needed for effective hemostasis.

12.2 Pharmacodynamics

The activated partial thromboplastin time (aPTT) is prolonged in people with hemophilia B. Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX. The administration of BeneFIX increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients.

12.3 Pharmacokinetics

In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX (reconstituted with Sterile Water for Injection) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 previously treated patients after repeated administration of BeneFIX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data are presented in Table 4:

Table 4: Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and Month 6 in Previously Treated Patients with Hemophilia B
Abbreviations: AUC = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.

Parameter

Baseline
N = 24
Mean ± SD

Month 6
N = 23
Mean ± SD

Cmax (IU/dL)

54.5 ± 15.0

57.3 ± 13.2

AUC (IU∙hr/dL)

940 ± 237

923 ± 205

t1/2 (hr)

22.4 ± 5.3

23.8 ± 6.5

CL (mL/hr/kg)

8.47 ± 2.12

8.54 ± 2.04

Recovery
(IU/dL per IU/kg)

0.73 ± 0.20

0.76 ± 0.18

Pediatric Patients (<12 years)

A population pharmacokinetic model was developed using data collected in patients aged 7 months to 60 years who received single doses of BeneFIX ranging from 50 to 75 IU/kg. The parameters estimated using the final 2-compartment model are shown in Table 5. Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower recovery than adolescents and adults.

Table 5: Mean ± SD Pharmacokinetic Parameters Derived from Population Pharmacokinetic Analysis
Age GroupInfants (<2 years)Children
2 to <6 yr
Children
6 to <12 yr
Adolescents and Adults (≥12 years)
Abbreviations: SD = standard deviation; Vss = volume of distribution at steady-state.

Number of subjects

7

16

1

43

Clearance (mL/h/kg)

13.1 ± 2.1

13.1 ± 2.8

15.5

8.4 ± 2.4

Vss (mL/kg)

252 ± 35

257 ± 25

303

229 ± 57

Half-life (h)

15.6 ± 1.2

16.7 ± 1.9

16.3

23.1 ± 4.4

Recovery (IU/dL per IU/kg)

0.61 ± 0.10

0.60 ± 0.08

0.47

0.72 ± 0.19

Data from 57 PUP subjects who underwent repeat recovery testing for up to 60 months demonstrated that the average recovery was consistent over time, as shown in Figure 1.

Figure 1

Figure 1. Average Recovery over Time

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Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

BeneFIX temporarily replaces the missing clotting factor IX that is needed for effective hemostasis.

12.2 Pharmacodynamics

The activated partial thromboplastin time (aPTT) is prolonged in people with hemophilia B. Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX. The administration of BeneFIX increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients.

12.3 Pharmacokinetics

In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX (reconstituted with Sterile Water for Injection) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 previously treated patients after repeated administration of BeneFIX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data are presented in Table 4:

Table 4: Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and Month 6 in Previously Treated Patients with Hemophilia B
Abbreviations: AUC = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half-life; CL = clearance; SD = standard deviation.

Parameter

Baseline
N = 24
Mean ± SD

Month 6
N = 23
Mean ± SD

Cmax (IU/dL)

54.5 ± 15.0

57.3 ± 13.2

AUC (IU∙hr/dL)

940 ± 237

923 ± 205

t1/2 (hr)

22.4 ± 5.3

23.8 ± 6.5

CL (mL/hr/kg)

8.47 ± 2.12

8.54 ± 2.04

Recovery
(IU/dL per IU/kg)

0.73 ± 0.20

0.76 ± 0.18

Pediatric Patients (<12 years)

A population pharmacokinetic model was developed using data collected in patients aged 7 months to 60 years who received single doses of BeneFIX ranging from 50 to 75 IU/kg. The parameters estimated using the final 2-compartment model are shown in Table 5. Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower recovery than adolescents and adults.

Table 5: Mean ± SD Pharmacokinetic Parameters Derived from Population Pharmacokinetic Analysis
Age GroupInfants (<2 years)Children
2 to <6 yr
Children
6 to <12 yr
Adolescents and Adults (≥12 years)
Abbreviations: SD = standard deviation; Vss = volume of distribution at steady-state.

Number of subjects

7

16

1

43

Clearance (mL/h/kg)

13.1 ± 2.1

13.1 ± 2.8

15.5

8.4 ± 2.4

Vss (mL/kg)

252 ± 35

257 ± 25

303

229 ± 57

Half-life (h)

15.6 ± 1.2

16.7 ± 1.9

16.3

23.1 ± 4.4

Recovery (IU/dL per IU/kg)

0.61 ± 0.10

0.60 ± 0.08

0.47

0.72 ± 0.19

Data from 57 PUP subjects who underwent repeat recovery testing for up to 60 months demonstrated that the average recovery was consistent over time, as shown in Figure 1.

Figure 1

Figure 1. Average Recovery over Time

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