Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: ADYNOVATE is distributed in New Zealand by: Takeda New Zealand Limited, Level 10, 21 Queen Street, Auckland 1010, New Zealand, Phone 0508 169 077, www.takeda.com/en-au
Pharmacotherapeutic group: Blood and blood forming organs, antihemorrhagics, vitamin K and other hemostatis, blood coagulation factors, coagulation factor VIII
ATC Code: B02BD02
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to von Willebrand factor in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a X-chromosomal linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as results of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
The safety, efficacy, and PK of ADYNOVATE were evaluated in a multicentre, open-label, prospective, non-randomised, two-arm clinical trial that compared the efficacy of a twice weekly prophylactic treatment regimen to on-demand treatment and determined haemostatic efficacy in the treatment of bleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe haemophilia A received at least one infusion with ADYNOVATE. Twenty-five of the 137 subjects were adolescents (12 to less than 18 years of age).
Subjects received either prophylactic treatment (n=120) with ADYNOVATE at a dose of 40-50IU per kg twice weekly or on-demand treatment (n=17) with ADYNOVATE at a dose of 10-60IU per kg for a 6-month period. The mean (SD) dose per prophylaxis infusion was 44.4(3.9)IU per kg with a median dosing interval of 3.6 days. There were 91 out of 98 (93%) subjects previously treated prophylactically prior to enrolment, who experienced a reduction in dosing frequency during routine prophylaxis in the study, with a median reduction of 33.7% (approximately one more day between doses). One hundred eighteen of 120 (98%) prophylaxis subjects remained on the starting recommended regimen without dose adjustment, and 2 subjects increased their dose to 60IU/kg during prophylaxis due to bleeding in target joints.
A total of 518 bleeding episodes were treated with ADYNOVATE in the per-protocol population, i.e. dosed according to the protocol specific dosing requirements. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm & 157 (n=61 subjects) occurred in the prophylaxis arm. The median total dose to treat all bleeding episodes in the per-protocol population was 30.9 (Q1: 21.6; Q3: 45.3)IU per kg. The median dose per infusion to treat all bleeding episodes in the perprotocol population was 29 (Q1: 20.0; Q3: 39.2)IU per kg. The median dose per infusion to treat a minor, moderate, or severe/major bleeding episode in the per-protocol population was 25.5 (Q1: 16.9; Q3: 37.6)IU/kg, 30.9 (Q1: 23.0; Q3: 43.1)IU/kg, or 36.4 (Q1: 29.0; Q3: 44.5)IU/kg, respectively.
A total of 591 bleeding episodes were treated with ADYNOVATE in the treated population, which was identical to the safety analysis set of subjects assigned to routine prophylaxis or on-demand treatment with ADYNOVATE and who received at least one dose of the product. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 230 bleeding episodes (n=75 subjects) occurred in the routine prophylaxis arm. Efficacy in control of bleeding episodes is summarised in Table 3.
Table 3. Summary of efficacy in control of bleeding (Treated Population):
| Bleeding Episode Aetiology | All | Joint | Non-joint | |
|---|---|---|---|---|
| Number of bleeds treated | 591 | 455 | 136 | |
| Number of infusions to treat bleeding episodes | 1 infusions: | 85.4% | 85.9% | 83.8% |
| 2 infusions: | 10.8% | 10.8% | 11.0% | |
| Total (1 or 2 infusions) | 96.2% | 96.7% | 94.8% | |
| Rate of success to treat bleeding episodes* | Excellent or good | 95.3% | 95.8% | 93.4% |
* Excellent defined as full relief of pain and objective signs of bleeding cessation; Good defined as definite pain relief and/or improvement in signs of bleeding; Fair defined as probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution; None defined as no improvement or condition worsened.
A total of 120 subjects (treated population) received a twice a week regimen in the prophylaxis arm, and an additional 17 subjects were treated episodically in the on- demand arm. In the treated population, the median [mean] annualised bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [4.7] while on a twice a week prophylaxis regimen (Table 4). In the perprotocol population, the median [mean] annualised bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [3.7] while on a twice a week prophylaxis regimen. Using a negative binomial model to estimate the ABR, there was a significant reduction in the ABR (p <0.0001) for subjects in the prophylaxis arm compared to the on-demand arm.
Table 4. Annualised bleed rate by treatment for ≥12 years of age (Treated Population):
| Bleeding Episode Aetiology | On-Demand Treatment | Routine Prophylaxis Treatment | ||
|---|---|---|---|---|
| Median | Mean (SD) | Median | Mean (SD) | |
| Overall | 41.5 | 40.8 (16.3) | 1.9 | 4.7 (8.6) |
| Joint | 38.1 | 34.7 (15.1) | 0.0 | 2.9 (8.0) |
| Non-Joint | 3.7 | 6.1 (6.7) | 0.0 | 1.8 (3.0) |
| Spontaneous | 21.6 | 26.0 (19.6) | 0.0 | 2.9 (7.1) |
| Traumatic | 9.3 | 14.9 (15.3) | 0.0 | 1.8 (3.1) |
In the treated population, the median [mean] ABR for the 23 adolescent subjects age 12 to <18 years of age on routine prophylaxis was 2.1 [5.2] compared to a median [mean] ABR of 1.9 [4.6] for the 97 subjects 18 years and older. Reduction in ABR between the treatment arms was observed regardless of baseline subgroups examined, including age, presence or absence of target joints, and pre-study treatment regimen. The majority of the bleeding episodes during prophylaxis (95%) were of minor/moderate severity. Forty-five out of 120 subjects (38%) experienced no bleeding episodes and 68 out of 120 subjects (57%) experienced no joint bleeding episodes in the prophylaxis arm. Of those subjects who were compliant to regimen (per-protocol population), 40 out of 101 subjects (40%) experienced no bleeding episodes. All subjects in the on-demand arm experienced a bleeding episode, including a joint bleeding episode.
The safety and efficacy of ADYNOVATE was evaluated in a total of 73 paediatric PTPs with severe haemophilia A, of which 66 subjects were dosed (32 subjects aged <6 years and 34 subjects aged 6 to <12 years) in a separate paediatric study. The prophylactic regimen was 40 to 60IU/kg of ADYNOVATE twice a week. The median [mean] overall ABR was 2.0 [3.61] for the 66 subjects in the treated population and the median [mean] ABRs for spontaneous and joint bleeding episodes were both 0 [1.18 and 1.12, respectively]. Of the 66 subjects treated prophylactically, 25 (38%) experienced no bleeding episodes, 44 (67%) experienced no spontaneous bleeding episodes, and 48 (73%) experienced no joint bleeding episodes.
Of the 70 bleeding episodes observed during the paediatric study, 82.9% were controlled with 1 infusion and 91.4% were controlled with 1 or 2 infusions. Control of bleeding was rated excellent or good in 63 out of 70 (90%) bleeding episodes. The definitions of excellent or good in the paediatric study were unchanged as compared to the previously conducted prophylaxis study in adolescent and adult subjects.
The long-term safety and efficacy of Adynovate in prophylaxis and treatment of bleeding episodes was evaluated in 216 paediatric and adult PTPs with severe haemophilia A who had either previously participated in other Adynovate studies or were naive to Adynovate. In the treated population, subjects received a fixed-dose twice-weekly regimen of 40 to 50 IU/kg if aged ≥12 years or of 40 to 60 IU/kg if aged <12 years. The dose was adjusted up to 80 IU/kg twice weekly if required to maintain FVIII trough levels of >1%. Subjects that opted for a personalised (pharmacokineticallytailored) prophylactic regimen received doses up to 80 IU/kg per infusion that targeted FVIII trough levels of ≥3% at least twice weekly. Subjects aged ≥12 years on a twice-weekly regimen who had zero spontaneous bleeds during a consecutive 6-month period could switch to fixed-dose prophylaxis every 5 days. If these subjects continued to have zero spontaneous bleeds for an additional 6 months, they were eligible for dosing every 7 days. Overall, exposure was long-term at a mean (SD) of 195.4 (101.57) prophylactic exposure days (EDs) per subject. ABR per prophylactic regimen, bleeding site and etiology are presented in Table 5.
Table 5. Annualised bleed rate (ABR) by prophylactic regimen (ITT population):
| Bleeding site eiology | Twice-weekly (N=186) | Every 5 Days (N=56) | Every 7 Days (N=15) | PK-tailoreda (N=25) |
|---|---|---|---|---|
| Mean [Point Estimate 95% Confidence Interval] | ||||
| Overall | 2.2 [1.85-2.69] | 2.1 [1.54-2.86] | 2.7 [1.44-5.20] | 2.6 [1.70-4.08] |
| Joint | 1.2 [0.96-1.58] | 1.1 [0.81-1.55] | 2.0 [0.90-4.62] | 1.4 [0.91-2.17] |
| Non-joint | 1.0 [0.77-1.21] | 1.0 [0.60-1.55] | 0.8 [0.41-1.51] | 1.2 [0.65-2.10] |
| Spontaneous | 1.2 [0.92-1.56] | 1.3 [0.87-2.01] | 1.8 [0.78-4.06] | 1.0 [0.54-1.71] |
| Traumatic | 1.0 [0.83-1.28] | 0.7 [0.45-0.99] | 0.9 [0.41-1.91] | 1.6 [1.03-2.50] |
Point estimates and 95% confidence intervals obtained from a generalised linear model fitting a negative binomial distribution with logarithmic link function.
Subjects receiving doses in multiple regimens are included in summaries for multiple regimens.
N = Number of subjects included in the analysis
a Targeting FVIII activity trough levels of ≥3% of normal
Long-term haemostatic efficacy was evaluated in 910 bleeding episodes treated with Adynovate and was rated excellent or good in 88.5% of bleeding episodes. Across age categories and for both the fixed-dose and the PK-tailored dose regimen, >85% of bleed treatments were rated excellent or good. The majority of bleeding episodes were treated with one (74.0%) or two (15.4%) infusions. Overall, during long-term exposure at a mean (SD) of 195.4 (101.57) prophylactic EDs per subject (median 208.5 EDs), 16.7% (36/216) of subjects had no bleeding episodes during this extended period.
Haemostatic efficacy of long-term treatment was reflected in Patient Reported Outcomes (PROs). Among the study population ≥18 years who completed the Haemo-SYM questionnaire at baseline and study completion, 60.4% (55/91) reported an improvement in the total Haemo-SYM score (p-value = 0.0023).
The safety and efficacy of Adynovate was evaluated in a prospective, randomised, open-label multicenter study in 121 (115 randomised) adolescents (12-18 years old) and adult PTPs with severe haemophilia A for a 12 months treatment period. The study compared 2 PK-guided prophylactic dosing regimens of Adynovate that targeted Factor VIII trough levels of 1-3% dosed twice weekly (N=57) or 8-12% dosed every other day (N=58), by assessing the proportions of subjects achieving a total ABR of 0 in the second 6-month study period.
The average prophylactic doses administered in the 1-3% and 8-12 % trough arms were 3,866.1 IU/kg per year [mean (SD) infusions/week = 2.3 (0.58)] and 7,532.8 IU/kg per year [(mean (SD) infusions/week = 3.6 (1.18)], respectively. After dose adjustment during the first 6-month period of prophylaxis, median trough levels in the second 6-month period (based on the one-stage clotting assay and calculated to the end of the planned infusion interval) ranged from 2.10 IU/dL to 3.00 IU/dL in the 1-3% trough level arm and from 10.70 IU/dL to 11.70 IU/dL in the 8-12 % trough level arm, demonstrating that dosing in the 2 prophylaxis regimens was generally adequate to achieve and maintain the desired FVIII trough levels.
Although the primary endpoint was not reached, the proportion of subjects in the ITT patient population who had a total ABR of 0 during the second 6-month period was higher in the 8-12% trough level arm (62%; 95% CI=49% to 75%) than in the 1-3% trough level arm (42%; 95% CI=29% to 55%) with a p-value of 0.0545. In the per-protocol population of subjects who completed the second 6-month of prophylactic treatment and had no major deviations from the protocol affecting the study results, the difference between the proportions of subjects with a total ABR of 0 was significant, favouring the 8-12% trough arm with a point estimate (95% CI) of 2.423 (0.463; 4.383) and a p-value of 0.0154. The proportions of randomised subjects with total ABRs, spontaneous ABRs and spontaneous annualised joint bleeding rates (AJBRs) of 0 during the second 6-month study period are presented in Table 6.
Table 6. Annualised bleed rate (ABR) of 0, Second 6-month Study Period:
| Proportion of subjects without bleeding in 6 months [Point estimate 95% Confidence Interval] | ||
|---|---|---|
| ITT population | ||
| 1-3% Trough Level (N=57) | 8-12% Trough Level (N=58) | |
| Total ABR of 0 | 0.421 [0.292; 0.549] | 0.621 [0.491; 0.750] |
| Spontaneous ABR of 0 | 0.596 [0.469; 0.724] | 0.760 [0.645; 0.875] |
| Spontaneous AJBR of 0 | 0.649 [0.525; 0.773] | 0.850 [0.753; 0.947] |
ABR = Annualised bleeding rate, AJBR = Annualised joint bleeding rate
Annualised bleeding rate determined by dividing the number of bleeds by observation period in years.
| Proportion of subjects without bleeding in 6 months [Point estimate 95% Confidence Interval] | ||
|---|---|---|
| ITT population | ||
| 1-3% Trough Level (N=57) | 8-12% Trough Level (N=43) | |
| Total ABR of 0 | 0.404 [0.270; 0.549] | 0.674 [0.515; 0.809] |
| Spontaneous ABR of 0 | 0.596 [0.451; 0.730] | 0.814 [0.666; 0.916] |
| Spontaneous AJBR of 0 | 0.654 [0.509; 0.780] | 0.907 [0.779; 0.974] |
ABR = Annualised bleeding rate, AJBR = Annualised joint bleeding rate
Per-protocol population = all subjects who completed the second 6 months of prophylactic treatment and had no major deviations from the protocol affecting the study results.
Annualised bleeding rate determined by dividing the number of bleeds by observation period in years.
Total ABRs, spontaneous ABRs and spontaneous AJBRs during the second 6-month study period are presented in Table 7.
Table 7. Annualised bleed rate (ABR), Second 6-month Study Period:
| ITT population | ||||
|---|---|---|---|---|
| 1-3% Trough Level (N=57) | 8-12% Trough Level (N=53) | |||
| Median | Mean (SD) | Median | Mean (SD) | |
| Total ABR | 2.0 | 3.6 (7.5) | 0.0 | 1.6 (3.4) |
| Spontaneous ABR | 0.0 | 2.5 (6.6) | 0.0 | 0.7 (1.7) |
| Spontaneous AJBR | 0.0 | 2.0 (6.4) | 0.0 | 0.5 (1.7) |
ABR = Annualised bleeding rate, AJBR = Annualised joint bleeding rate
Annualised bleeding rate determined by dividing the number of bleeds by observation period in years.
| ITT population | ||||
|---|---|---|---|---|
| 1-3% Trough Level (N=57) | 8-12% Trough Level (N=53) | |||
| Median | Mean (SD) | Median | Mean (SD) | |
| Total ABR | 2.0 | 2.8 (3.0) | 0.0 | 1.2 (2.4) |
| Spontaneous ABR | 0.0 | 1.7 (2.5) | 0.0 | 0.6 (1.5) |
| Spontaneous AJBR | 0.0 | 1.2 (2.0) | 0.0 | 0.4 (1.4) |
ABR = Annualised bleeding rate, AJBR = Annualised joint bleeding rate
Per-protocol population = all subjects who completed the second 6 months of prophylactic treatment and had no major deviations from the protocol affecting the study results.
Annualised bleeding rate determined by dividing the number of bleeds by observation period in years.
A total of 242 bleeding episodes in 66 subjects were treated with Adynovate; 155 bleeds in 40 subjects in the 1-3% trough level arm and 87 bleeds in 26 subjects in the 8-12% trough level arm. The majority of bleeds (86.0%, 208/242) were treated with 1 or 2 infusions; and bleed treatment at resolution of the bleeding episode was rated excellent or good in 84.7% (205/242) of bleeds.
Haemostatic efficacy in the prevention and treatment of bleeds was reflected in the patient-reported outcomes with improvements between baseline and study completion in the Short Form-36 Physical Component Score administered to subjects ≥14 years of age, and in the Haemo-SYM bleed and pain severity scores administered to subjects ≥18 years of age.
A total of 26 procedures, 21 major and 5 minor were performed in 21 unique subjects between 16 and 61 years of age. The 21 major surgeries comprised 14 orthopaedic (3 knee replacements, 1 hip replacement, 1 hip replacement revision, 3 arthroscopic synovectomies, 1 elbow cyst extirpation, 1 needle removal from the elbow, 3 alloplastic knee surgeries and 1 Achilles tendon reconstruction) and 7 non-orthopaedic procedures (5 dental, 1 cardiovascular and 1 abdominal). The 5 minor surgeries comprised 2 dermatological, 1 orthopaedic and 1 dental procedure, and 1 radio synovectomy. The preoperative loading dose ranged from 36 IU/kg to 99 IU/kg (median: 60 IU/kg) and the total postoperative dose ranged from 23 IU/kg to 769 IU/kg (median: 183 IU/kg). The median total dose for major orthopaedic surgeries was 629 IU/kg (range: 464-1457 IU/kg, the median total dose for major non-orthopaedic surgeries was 489 IU/kg (range: 296-738 IU/kg) and the median total dose for minor surgeries was 120 IU/kg (range: 104-151 IU/kg).
Perioperative haemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the same type of procedure performed in a non-haemophilic patient, and required blood components for transfusions less than or similar to that expected in non-haemophilic population) for all 24 (21 major, 3 minor) procedures with available assessments.
The pharmacokinetics (PK) of ADYNOVATE were evaluated in a crossover study with ADVATE in 26 subjects (18 adults and 8 adolescents) and in 22 subjects (16 adults and 6 adolescents) after 6 months of treatment with ADYNOVATE. A single dose of 45 ± 5IU/kg was utilised for both products. In the paediatric study, a single dose of 60 ± 5IU/kg was utilised for both ADVATE and ADYNOVATE to evaluate PK in 31 paediatrics subjects (<6 years and 6 to <12 years of age). Plasma factor VIII activity was measured by the one-stage clotting assay & chromogenic assay as shown in Tables 8-11.
ADYNOVATE has an extended half-life of 1.4 to 1.5-fold compared to recombinant full-length human coagulation factor VIII (ADVATE) in the adolescent and adult population, as determined based on one-stage clotting and chromogenic assays, respectively. The half-life extension in the paediatric population was 1.3 to 1.5 fold using both the one stage clotting and chromogenic assays. An increase in AUC and a decrease in clearance as compared to the parent molecule, ADVATE, were also observed. Incremental recovery was comparable with both products. The change in PK parameters was similar in both the adult and adolescent populations and between one-stage clotting and chromogenic substrate assays.
Table 8. Pharmacokinetic parameters in adults using the one-stage clotting assay (arithmetic mean ± SD):
| PK Parameters | ADVATE N=18 | ADYNOVATE N=18 |
|---|---|---|
| Design | Individual PK with full samplinga | |
| Terminal half-life [h] | 10.83 ± 2.08 | 14.69 ± 3.79 |
| MRT [h] | 13.41 ± 3.00 | 20.27 ± 5.23 |
| CL [mL/(kg·h)] | 3.88 ± 1.24 | 2.27 ± 0.84 |
| Incremental Recovery [(IU/dK)/(IU/kg)] | 2.57 ± 0.43 | 2.66 ± 0.68 |
| AUC0-Inf [IU·h/dL] | 1286 ± 390 | 2264 ± 729 |
| VSS [dL/kg] | 0.50 ± 0.11 | 0.43 ± 0.11 |
| Cmax [IU/dL] | 117 ± 20 | 122 ± 29 |
| Tmax [h] | 0.33 ± 0.19 | 0.46 ± 0.29 |
Abbreviations: CI: confidence interval; Cmax: maximum observed activity; AUC: area under the curve; MRT: mean residence time; CL: clearance; Vss: body weight adjusted volume of distribution at steady-state, Tmax: time to reach the maximum concentration.
a Individual PK with 12 post-infusion samples.
Table 9. Pharmacokinetic parameters in adults using the chromogenic assay (arithmetic mean ± SD):
| PK Parameters | ADVATE N=18 | ADYNOVATE N=18 |
|---|---|---|
| Design | Individual PK with full samplinga | |
| Terminal half-life [h] | 10.43 ± 3.41 | 15.01 ± 3.90 |
| MRT [h] | 13.00 ± 3.87 | 19.70 ± 5.05 |
| CL [mL/(kg·h)] | 3.95 ± 1.37 | 1.97 ± 0.70 |
| Incremental Recovery [(IU/dK)/(IU/kg)] | 2.74 ± 0.39 | 3.16 ± 0.68 |
| AUC0-Inf [IU·h/dL] | 1281 ± 424 | 2589 ± 849 |
| VSS [dL/kg] | 0.48 ± 0.14 | 0.37 ± 0.08 |
| Cmax [IU/dL] | 125 ± 17 | 145 ± 29 |
| Tmax [h] | 0.26 ± 0.12 | 0.32 ± 0.16 |
Abbreviations: CI: confidence interval; Cmax: maximum observed activity; AUC: area under the curve; MRT: mean residence time; CL: clearance; Vss: body weight adjusted volume of distribution at steady-state, Tmax: time to reach the maximum concentration.
a Individual PK with 12 post-infusion samples.
Pharmacokinetic parameters calculated from 39 subjects less than 18 years of age (intent-to-treat analysis) are available for 14 children (1 to less than 5 years), 17 older children (6 to less than 12 years) and 8 adolescent subjects (12 to <18 years of age), as shown in Table 10. The mean clearance (based on body weight) of ADYNOVATE was higher and the mean half-life was lower in children less than 12 years of age than adults. A higher dose may be required in children less than 12 years of age.
Table 10. Summary of pharmacokinetic parameters of ADYNOVATE for paediatrics using the one-stage clotting assay:
| Parameter (mean ± standard deviation) | Paediatric Study | Pivotal Study in adolescents & adults | ||
|---|---|---|---|---|
| <6 years (n=14) | 6 to <12 years (n=17) | 12 to <18 years (n=8) | ||
| Design | Population PK with sparse samplinga | Individual PK with full samplingb | ||
| Terminal half-life [h] | 11.8 ± 2.43 | 12.4 ± 1.67 | 13.43 ± 4.05 | |
| MRT [h] | 17.0 ± 3.50 | 17.8 ± 2.42 | 17.96 ± 5.49 | |
| CL [mL/(kg·h)] | 3.53 ± 1.29 | 3.11 ± 0.76 | 3.87 ± 3.31 (2.73 ± 0.93)d | |
| Incremental Recovery [(IU/dK)/(IU/kg)] | 1.89 ± 0.49 | 1.95 ± 0.47 | 2.12 ± 0.60 | |
| AUC0-Inf [IU·h/dL] | 1947 ± 757 | 2012 ± 495 | 1642 ± 752 | |
| VSS [dL/kg] | 0.56 ± 0.12 | 0.54 ± 0.09 | 0.56 ± 0.18 | |
| Cmax [IU/dL] | 115 ± 30 | 115 ± 33 | 95 ± 25 | |
| Tmax [h] | -c | -c | 0.26 ± 0.10 | |
Abbreviations: CI: confidence interval; Cmax: maximum observed activity; AUC: area under the curve; MRT: mean residence time; CL: clearance; Vss: body weight adjusted volume of distribution at steady-state, Tmax: time to reach the maximum concentration
a Population PK model with 3 post-infusion samples based on randomised drawing schedule
b Individual PK with 12 post-infusion samples.
c Tmax could not be calculated for subjects in the paediatric study as only one sample was drawn (15-30 minutes post-infusion) within the first 3 hours of the infusion.
d Estimated mean and SD calculated not including one subject whose clearance estimate was 11.8mL/(kg·h). Median including all subjects is 2.78 mL/(kg·h).
Table 11. Summary of pharmacokinetic parameters of ADYNOVATE for paediatrics using the chromogenic assay:
| Parameter (mean ± standard deviation) | Paediatric Study | Pivotal Study in adolescents & adults | ||
|---|---|---|---|---|
| <6 years (n=14) | 6 to <12 years (n=17) | 12 to <18 years (n=8) | ||
| Design | Population PK with sparse samplinga | Individual PK with full samplingb | ||
| Terminal half-life [h] | 12.99 ± 8.75 | 11.93 ± 2.58 | 13.80 ± 4.01 | |
| MRT [h] | 18.74 ± 12.60 | 17.24 ± 3.72 | 17.73 ± 5.44 | |
| CL [mL/(kg·h)] | 3.49 ± 1.21 | 2.80 ± 0.67 | 2.58 ± 0.84 | |
| Incremental Recovery [(IU/dK)/(IU/kg)] | NAc (1.90 ± 0.27) | NAc (2.19 ± 0.40) | 2.34 ± 0.62 | |
| AUC0-Inf [IU·h/dL] | 2190 ± 1593 | 2259 ± 514 | 1900 ± 841 | |
| VSS [dL/kg] | 0.54 ± 0.03 | 0.46 ± 0.04 | 0.54 ± 0.22 | |
| Cmax [IU/dL] | NAc (117 ± 16) | NAc (130 ± 24) | 117 ± 28 | |
| Tmax [h] | -e | -e | 0.26 ± 0.14 | |
Abbreviations: CI: confidence interval; Cmax: maximum observed activity; AUC: area under the curve; MRT: mean residence time; CL: clearance; Vss: body weight adjusted volume of distribution at steady-state, Tmax: time to reach the maximum concentration
a Population PK model with 3 post-infusion samples based on randomised drawing schedule.
b Individual PK with 12 post-infusion samples.
c NA, Not applicable, as Incremental Recovery and Cmax in children were determined by individual PK. Results for Incremental Recovery and Cmax determined by individual PK in parenthesis.
d The clearance value of 12.18 mL (kg.h) for subject 122001 in age group 12 to <18 years was not included in the analysis of clearance.
e Tmax could not be calculated for subjects in the paediatric study as only one sample was drawn (15-30 minutes post-infusion) within the first 3 hours of the infusion
The PK data demonstrates that ADYNOVATE has an extended circulating half-life.
No studies on Genotoxicity have been performed with ADYNOVATE.
No studies on carcinogenicity have been performed with ADYNOVATE.
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