Source: Health Products and Food Branch (CA) Revision Year: 2021
Eloctate (Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein) is a fully recombinant fusion protein comprised of recombinant B domain-deleted human Factor VIII (BDD FVIII) covalently linked to the Fc domain of human immunoglobulin G1 (IgG1) and produced by recombinant DNA technology.
The FVIII portion of Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein is a glycoprotein comparable to the 90+80 kDa form of endogenous FVIII that is found in human plasma.
The other portion of Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein) is the Fc region of human immunoglobulin G1 (IgG1) that binds to the neonatal Fc receptor (FcRn). This receptor is expressed throughout life and is part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life. Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein binds to FcRn thereby utilizing this same naturally occurring pathway to delay lysosomal degradation and allow for longer plasma half-life than endogenous FVIII.
Eloctate is used as a replacement therapy to increase plasma levels of factor VIII, thereby enabling a temporary correction of the factor deficiency and the bleeding tendency.
Hemophilia A is a bleeding disorder characterized by a deficiency of functional clotting factor VIII (FVIII), which leads to prolonged clotting time in the activate partial thromboplastin time (aPTT) assay, a conventional in vitro test for the biological activity of FVIII. Treatment with Eloctate normalizes the clotting time over the effective dosing period.
The pharmacokinetics of ELO Eloctate CTATE compared with Advate (Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method) was evaluated following a 10-minute IV infusion in 28 evaluable subjects (≥15 years) in Study 1. The subjects underwent a washout period of at least 4 days prior to receiving 50 IU/kg of Advate. Pharmacokinetic sampling was conducted pre-dose followed by assessments at 6 time points up to 72 hours (3 days) post-dose. Following a washout period of 96 hours (4 days), the subjects received a single dose of 50 IU/kg of Eloctate. Pharmacokinetic samples were collected pre-dose and then subsequently at 7 time points up to 120 hours (5 days) post-dose. A repeat pharmacokinetic evaluation of Eloctate was conducted at week 14.
The pharmacokinetic parameter results (Table 6) were based on plasma FVIII activity measured by the one-stage clotting assay. The pharmacokinetic profiles of 27 patients were obtained at week 14, after repeat dosing, and were comparable with the pharmacokinetic profiles obtained after the first dose. The pharmacokinetic data demonstrate that Eloctate has a prolonged circulating half-life.
Table 6. Summary of Pharmacokinetic Parameters of Eloctate and Advate:
| PK Parameters1 | Eloctate (95% CI) | Advate (95% CI) | Ratio of Eloctate to Advate (95% CI) |
|---|---|---|---|
| N=28 | N=28 | N=28 | |
| Cmax (IU/dL) | 108 (101, 115) | 120 (111, 128) | 0.90 (0.86, 0.95) |
| AUC/Dose (IU*h/dL per IU/kg) | 51.2 (45.0, 58.4) | 32.9 (29.3, 36.9) | 1.56 (1.46, 1.67) |
| t1/2 (h) | 19.0 (17.0, 21.1) | 12.4 (11.1, 13.9) | 1.53 (1.36, 1.71) |
| CL (mL/h/kg) | 1.95 (1.71, 2.22) | 3.04 (2.71, 3.41) | 0.64 (0.60, 0.69) |
| MRT (h) | 25.2 (22.7, 27.9) | 16.8 (15.2, 18.6) | 1.49 (1.41, 1.58) |
| Vss (mL/kg) | 49.1 (46.6, 51.7) | 51.2 (47.2, 55.5) | 0.96 (0.90, 1.02) |
| Incremental Recovery (IU/dL per IU/kg) | 2.24 (2.11, 2.38) | 2.35 (2.21, 2.50) | 0.95 (0.91, 0.99) |
| Time to 1% (days) | 4.92 (4.434. 5.46) | 3.30 (2.99, 3.65) | 1.49 (1.41, 1.57) |
1 PK parameters are presented in Geometric Mean (95% CI) Abbreviations: CI = confidence interval; Cmax= maximum activity; AUC = area under the FVIII activity time curve; t1/2 = terminal half-life; CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state
Pharmacokinetic (PK) parameters of Eloctate were determined for adolescents 12 to <18 years of age in Study 1 and for children <12 years of age in Study 2 (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).
PK parameters were evaluated following a 10-minute IV infusion in 11 evaluable adolescents who received a single dose of Eloctate. PK samples were collected pre-dose and then at multiple time points up to 120 hours (5 days) post-dose. In a separate study (Study 2), PK parameters were evaluated following a 5-minute IV infusion in 54 evaluable children <12 years of age who received a single dose of Eloctate. PK samples were collected pre-dose and then at multiple time points up to 72 hours (3 days) post-dose. In pediatric subjects <12 years of age on previous Advate therapy (n=15), half-life prolongation of Eloctate relative to Advate (approximately 1.5 fold) is consistent with adult and adolescent subjects.
Table 7 presents the PK parameters calculated from the data of 65 subjects <18 years of age. Compared to adults and adolescents clearance appeared to be higher and half-life appeared to be shorter in children <12 years of age. This may result in a need for dose adjustments in children <12 years of age (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).
Table 7. Comparison of PK Parameters of Eloctate by Age:
| PK Parameters1 | Study 2 | Study 1 | |
|---|---|---|---|
| <6 Years | 6 to <12 Years | 12 to <18 Years | |
| N=23 | N=31 | N=11 | |
| IR (IU/dL per IU/kg) | 1.90 (1.79, 2.02) | 2.30 (2.04, 2.59) | 1.81 (1.56, 2.09) |
| AUC/Dose (IU*h/dL per IU/kg) | 28.9 (25.6, 32.7) | 38.4 (33.2, 44.4) | 38.2 (34.0, 42.9) |
| t½ (h) | 12.3 (11.0, 13.7) | 13.5 (11.4, 15.8) | 16.0 (13.9, 18.5) |
| MRT (h) | 16.8 (15.1, 18.6) | 19.0 (16.2, 22.3) | 22.7 (19.7, 26.1) |
| CL (mL/h/kg) | 3.46 (3.06, 3.91) | 2.61 (2.26, 3.01) | 2.62 (2.33, 2.95) |
| Vss (mL/kg) | 57.9 (54.1, 62.0) | 49.5 (44.1, 55.6) | 59.4 (52.7, 67.0) |
1 PK parameters are presented in Geometric Mean (95% CI)
Abbreviations: IR = incremental recovery; CI = confidence interval; Cmax= maximum activity; AUC = area under the FVIII activity time curve; t1/2 = terminal half-life; CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized (see DOSAGE AND ADMINISTRATION).
No formal pharmacokinetic studies have been conducted to examine the effects of hepatic impairment on Eloctate disposition.
No formal pharmacokinetic studies have been conducted to examine the effects of renal impairment on Eloctate disposition.
No microbiological information is required for this drug product.
Results of repeat-dose studies in two animal species, rats and monkeys, using IV administration, revealed no safety findings relevant to use in humans. Rats were dosed for 4 weeks while monkeys were dosed for 4 weeks in 2 separate studies. The highest dose, 1000 IU/kg, provides a safety margin of 20-fold relative to a starting dose of 50 IU/kg for patients and a 10-fold relative to a starting dose of 100 IU/kg for patients.
| Study Number and Title | Species | Dose and Frequency | Key Findings |
|---|---|---|---|
| Repeat-Dose Toxicology Studies | |||
| Four-Week IV Dose Toxicity and PK Study of FVIIIFc in Rats Followed by a 4-Week Recovery Period | Sprague Dawley Rats | 0, 50, 250 and 1000 IU/kg (liquid formulation) IV every 2 days for 4 weeks (14 doses) | Repeat doses were welltolerated. Antibodies to Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein (~80% to 90% at all dose levels). ~25% increase in aPTT on SD29. NOAEL was 1000 IU/kg. |
| Four-Week IV Dose Toxicity and PK Study of FVIIIFc in Cynomolgus Monkeys Followed by a 4-Week Recovery Period | Cynomolgus Monkeys | 0, 50, 250 and 1000 IU/kg (liquid formulation) IV every 2 days for 4 weeks (14 doses) | Dose-related increases in antibodies to Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein and dose-related increases in aPTT. Dose-related increases in bruising and SC hemorrhage following blood collection. 3 moribund sacrifices at 1000 IU/kg (after the last dose). NOAEL was 1000 IU/kg for direct toxicological effects. |
| Four-Week IV Dose Toxicity and PK Study of FVIIIFc Lyophilized DP in Cynomolgus Monkeys Followed by a 4-Week Recovery Period | Cynomolgus Monkeys | 0, 50, 250 and 1000 IU/kg (lyophilized formulation) IV every 2 days for 4 weeks (14 doses) | Dose-related increases in antibodies to Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein and dose-related increases in aPTT. Dose-related increases in bruising and SC hemorrhage following blood collection. There were no moribund sacrifices. NOAEL was 1000 IU/kg for direct toxicological effects. |
aPTT = activated partial thromboplastin time; DP = drug product; IV = intravenous; NOAEL = no observed adverse effect level; SC = subcutaneous; SD = study day
Eloctate has not been evaluated in animal reproductive studies. No impact on male or female reproductive organs was shown in toxicology studies in rats and monkeys. In a placental transfer study, Eloctate has been shown to cross the placenta in small amounts in mice.
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