Moroctocog alfa is a B-domain deleted recombinant coagulation factor VIII. It is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. Moroctocog alfa has functional characteristics comparable to those of endogenous factor VIII. Factor VIII activity is greatly reduced in patients with haemophilia A, and, therefore, replacement therapy is necessary.
When infused into a haemophiliac patient, factor VIII binds to the von Willebrand factor present 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 is formed.
Haemophilia A is a sex-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 a result 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.
Pharmacokinetic properties of moroctocog alfa, derived from a cross-over study of moroctocog alfa and a plasmaderived FVIII concentrate, using the chromogenic substrate assay, in 18 previously treated patients are listed in the table below.
Pharmacokinetic parameter estimates for moroctocog alfa in previously treated patients with haemophilia A:
| PK parameter | Mean | SD | Median |
|---|---|---|---|
| AUCt (IU∙h/ml) | 19.9 | 4.9 | 19.9 |
| t1/2 (h) | 14.8 | 5.6 | 12.7 |
| CL (ml/h∙kg) | 2.4 | 0.75 | 2.3 |
| MRT (h) | 20.2 | 7.4 | 18.0 |
| recovery (IU/dl increase in FVIII:C per IU/kg FVIII given) | 2.4 | 0.38 | 2.5 |
Abbreviations: AUCt = area under the plasma concentration-time curve from zero to the last measurable concentration; t½ = half-life; CL = clearance; FVIII:C = FVIII activity; MRT = mean residence time
In a cross-over pharmacokinetic study, the pharmacokinetic parameters for moroctocog alfa were determined at baseline and followed up in 25 previously treated patients (≥12 years) after repeated administration of moroctocog alfa for six months. The ratios of geometric least-square means of month 6-to-baseline pharmacokinetic were 107%, 100% and 104% for recovery, AUCt and AUC∞, respectively. The corresponding 90% confidence intervals about the ratios of month 6-to-baseline for the above pharmacokinetic parameters were within the equivalence window of 80% to 125%. This indicates no time-dependent changes in the pharmacokinetic properties of moroctocog alfa.
In the same study, in which the drug potency of moroctocog alfa and a full-length recombinant factor VIII (FLrFVIII) comparator, and the FVIII activity measured in patient plasma samples were all determined using the same one-stage clotting assay at a central laboratory, moroctocog alfa was shown to be pharmacokinetically equivalent to FLrFVIII in 30 previously treated patients (≥12 years) using the standard bioequivalence approach.
In PUPs, pharmacokinetic parameters of moroctocog alfa were evaluated using the chromogenic assay. These patients (n=59; median age 10 ± 8.3 months) had a mean recovery at Week 0 of 1.5 ± 0.6 IU/dl per IU/kg (range 0.2 to 2.8 IU/dl per IU/kg) which was lower than that obtained in PTPs treated with moroctocog alfa at Week 0 with a mean recovery of 2.4 ± 0.4 IU/dl per IU/kg (range 1.1 to 3.8 IU/dl per IU/kg). In the PUPs, the mean recovery was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dl per IU/kg. Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of 8.0 ± 2.2 hours.
In a moroctocog alfa study of 19 PUPs, the recovery at the beginning of the study in the 17 children aged 28 days to less than 2 years was 1.32 ± 0.65 IU/dl per IU/kg and in the 2 children aged 2 to <6 years were 1.7 and 1.8 IU/dl per IU/kg. Except in cases where inhibitors were detected, the mean recovery was stable over time (6 visits during a 2-year period) and individual values ranged from 0 (in presence of inhibitor) to 2.7 IU/dl per IU/kg.
In a study of 37 paediatric PTPs, the pharmacokinetic parameters of moroctocog alfa observed after a 50 IU/kg dose are shown in the table below.
Mean ± SD FVIII Pharmacokinetic Parameters after Single 50 IU/kg Dose in Paediatric PTPs:
| PK parameter | Number of subjects | Meana ± SD |
|---|---|---|
| Recovery, IU/dl per IU/kg Aged <6 years | 17 | 1.7 ± 0.4 |
| Recovery, IU/dl per IU/kg Aged 6 to <12 years | 19 | 2.1 ± 0.8 |
| Cmax, IU/mLb | 19 | 0.9 (45) |
| AUCinf, IU∙h/mLβ | 14 | 9.9 (41) |
| t1⁄2, hb | 14 | 9.1 ± 1.9 |
| CL, mL/h/kgb | 14 | 4.4 (30) |
| Vss, mL/kgb | 14 | 56.4 (15) |
a Geometric mean (geometric CV%) for all, except for arithmetic mean ±SD for incremental recovery and t½.
b Patients aged 6 to <12 years only.
Abbreviations: Cmax = maximum observed plasma concentration; CV = coefficient of variation; AUCinf = area under the plasma concentration-time profile from time zero extrapolated to infinite time; t½ = terminal half-life; CL = clearance; Vss = steady-state volume of distribution.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.
No investigations on carcinogenic potential or toxicity to reproduction have been conducted.
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