Turoctocog alfa is a B domain truncated human recombinant FVIII for treatment of patients with hemophilia A. The production yields a highly homogenous product with the same tyrosine sulphation as human FVIII. In order to confirm the consistency of turoctocog alfa pharmacokinetics (PK) over different production lots and vial strengths, a clinical trial was performed in 15 patients with severe hemophilia A.
To compare the PK of 3 lots of 2000 IU/vial and 1 lot of 3000 IU/vial of turoctocog alfa after i.v. administration of 50 IU/kg in patients with severe haemophilia A.
This was a multi-centre, open-label trial investigating the PK of 4 lots of turoctocog alfa (3 lots of 2000 IU/vial; Lots A, B and C, and 1 lot of 3000 IU/vial; Lot D) in patients with severe hemophilia A (FVIII<1%). The trial was performed as a two-period, incomplete block, cross-over trial, in which each patient was allocated at random to a predefined sequence of 2 different lots of turoctocog alfa.
The FVIII activity was assessed using both the one-stage clot and chromogenic assays. Both the primary endpoint, normalized AUC (AUC*(planned dose/actual dose)), and the secondary PK endpoints were analyzed by ANCOVA on the log transformed values, with lot, visit and patient as fixed effects. Each of the three 2000 IU/vial lots was compared and tested against the 2 other 2000 IU/vial lots. If not significantly different on a 5% level, the 3 lots were pooled together and tested against the 3000 IU/vial lot.
Fifteen patients with a mean age of 38.6 years (ranging from 21 to 60 years) were included from 3 hemophilia centres in 3 different countries. Three adverse events (AEs) were reported in the trial by 2 separate patients; all AEs were judged to be unlikely related to the trial product. There was no development of inhibitors.
There was no pharmacokinetic difference observed between Lots A, B, C (2000 IU/vials) and there was no pharmacokinetic difference observed between the pooled data from lot A, B and C (2000 IU/vial) and lot D (3000 IU/vial) based on normalized AUC, half-life, incremental recovery and clearance. The estimated mean values (with 90% CI) for the PK parameters based on the chromogenic assay are presented in Table 1. The results were similar for the one-stage clot assay and the chromogenic assay.
PK parameters (estimated mean and 90% CI) for the 4 different lots of turoctocog alfa (based on the chromogenic assay)
| PK parameter . | Lot A . | Lot B . | Lot C . | Lot D . |
|---|---|---|---|---|
| 2000 IU/vial . | 2000 IU/vial . | 2000 IU/vial . | 3000 IU/vial . | |
| Normalized AUC IU*h/mL | 20.51 (18.23; 23.06) | 24.01 (21.34; 27.00) | 22.02 (19.76; 24.55) | 22.73 (20.39; 25.33) |
| Incremental recovery (IU/mL)/(IU/kg) | 0.028 (0.024; 0.031) | 0.031 (0.027; 0.035) | 0.028 (0.025; 0.032) | 0.030 (0.027; 0.034) |
| Half-life h | 11.16 (10.67; 11.68) | 11.25 (10.75; 11.76) | 11.19 (10.73; 11.67) | 10.73 (10.29; 11.19) |
| Clearance mL/h/kg | 2.44 (2.17; 2.74) | 2.08 (1.85; 2.34) | 2.27 (2.04; 2.53) | 2.20 (1.97; 2.45) |
| PK parameter . | Lot A . | Lot B . | Lot C . | Lot D . |
|---|---|---|---|---|
| 2000 IU/vial . | 2000 IU/vial . | 2000 IU/vial . | 3000 IU/vial . | |
| Normalized AUC IU*h/mL | 20.51 (18.23; 23.06) | 24.01 (21.34; 27.00) | 22.02 (19.76; 24.55) | 22.73 (20.39; 25.33) |
| Incremental recovery (IU/mL)/(IU/kg) | 0.028 (0.024; 0.031) | 0.031 (0.027; 0.035) | 0.028 (0.025; 0.032) | 0.030 (0.027; 0.034) |
| Half-life h | 11.16 (10.67; 11.68) | 11.25 (10.75; 11.76) | 11.19 (10.73; 11.67) | 10.73 (10.29; 11.19) |
| Clearance mL/h/kg | 2.44 (2.17; 2.74) | 2.08 (1.85; 2.34) | 2.27 (2.04; 2.53) | 2.20 (1.97; 2.45) |
No pharmacokinetic differences were observed between the three 2000 IU/vial lots (Lot A, Lot B and Lot C), nor were there pharmacokinetic differences between Lot D (3000 IU/vial) and pooled data from Lots A, B and C, based on normalized AUC, half-life, incremental recovery and clearance. There were no safety concerns and no inhibitor development in the trial.
Jiménez-Yuste:Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Klamroth:Novo Nordisk, CSL Behring, Bayer, Baxter, Pfizer: Honoraria, Research Funding. Saugstrup:Novo Nordisk: Employment. Moss:Novo Nordisk: Employment.
