The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose recombinant activated factor VII in patients with haemophilia A or B.

Monitoring recombinant activated factor VII (rFVIIa) treatment outcomes remains challenging. Thromboelastography (TEG) and the thrombin generation assay (TGA), measure coagulation dynamics over time and are being assessed as potential methods for evaluating and monitoring haemophilia treatment. Lack of standardized TEG/TGA methods makes it difficult to compare results and to establish a correlation with clinical outcomes. AIMS: To compare the pharmacokinetics (PK) of rFVIIa after 3×90 µg kg-1 doses vs a single dose (270 µg kg-1 ) in haemophilia patients and to evaluate TEG/TGA results postdosing to determine how these assays relate to PK findings. METHODS: Patients in this open-label, single-centre, randomized, crossover trial received one injection of 270 µg kg-1 rFVIIa crossed over with three injections of 90 µg kg-1 rFVIIa in a non-bleeding state. For TEG, kaolin and tissue factor were used as activators; TGA was performed on frozen platelet-rich and platelet-poor plasma, with and without corn trypsin inhibitor. FVIIa activity was evaluated using in vivo samples. RESULTS: TGA showed a dose-dependent effect of rFVIIa on thrombin generation; TEG revealed lower dose-dependent effects. Both showed some differences between single-/multiple-dose rFVIIa; both supported the PK findings. CONCLUSION: While TEG and TGA are not yet clinically predictive, both supported the PK results. Data suggest that, while a single dose of 270 µg kg-1 rFVIIa provides slightly higher haemostatic potential than the multiple-dose regimen of 3×90 µg kg-1 , the latter results in prolonged activity levels compared with a higher single dose.

Pharmacokinetics of recombinant factor XIII in young children with congenital FXIII deficiency and comparison with older patients.

Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder, which in its severe form is associated with a significant bleeding phenotype, requiring regular prophylactic therapy. A recently developed recombinant FXIII (rFXIII) has demonstrated safety and efficacy in children aged ≥6 years and adults (mentor1 trial). This article describes the mentor4 trial, which has assessed the pharmacokinetics (PK) and safety of rFXIII in younger children (1 to <6 years) with congenital FXIII deficiency, and compares extrapolated PK parameters with the mentor1 trial. Six children with congenital FXIII A-subunit deficiency received a single, 35 IU kg(-1) rFXIII dose. PK properties were similar in all the children, with a mean area under the concentration vs. 30-day time curve of 248.6 IU h(-1) mL(-1) , maximal FXIII activity (30 min) of 0.67 IU mL(-1) , and mean 30-day trough of 0.21 IU mL(-1) . All patients maintained FXIII activity above the lower target level (0.1 IU mL(-1) ). rFXIII half-life was 15.1 days (range, 10-25). No safety findings of clinical concern were observed. PK properties of rFXIII were similar in patients from both trials. The study demonstrated that a single dose of 35 IU kg(-1) rFXIII maintained plasma FXIII levels above 0.1 IU mL(-1) over a 30-day period in young children with congenital FXIII deficiency, and is, therefore, likely to provide adequate prophylaxis in this age group. The study extends the previous findings of the mentor1 trial and confirms that no dose adjustment is required for different age groups with congenital FXIII deficiency.

Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa).

BACKGROUND: Recombinant activated factor VIIa (rFVIIa) is used to treat bleeds in hemophilia patients with inhibitors. A subcutaneous formulation could potentially improve its half-life and make it suitable for prophylactic treatment. OBJECTIVES: A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability). PATIENTS/METHODS: This was a multicenter, open-label, cross-over comparison of single doses of intravenous rFVIIa 90µgkg(-1) and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360µgkg(-1) . Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled. RESULTS: Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (C(max) , 0.44-5.16IU mL(-1) [across doses]; t(1/2) , 12.4h; t(max) , 5.6h) compared with intravenously administered rFVIIa (C(max) , 51.7IUmL(-1) ; t(1/2) , 2.7h; t(max) , <10min). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1 to 30.1% across dose levels. Dose proportionality was observed within a 2-fold dose increase but not across the full dose range. No thromboembolic events, drug-related serious adverse events, severe injection-site reactions or neutralizing antibodies were reported (primary endpoint). Mild and moderate injection-site reactions were more frequent with subcutaneous than with intravenous injections. CONCLUSION: This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.

Intra-patient variability of thromboelastographic parameters following in vivo and ex vivo administration of recombinant activated factor VII in haemophilia patients. A multi-centre, randomised trial.

Thromboelastography methods have been used to predict or monitor treatment of haemophilia patients with recombinant activated factor VII (rFVIIa). However, neither of the two thromboelastographic methods (ROTEM and TEG) has as yet been validated. This multi-centre, randomised trial compared both methods in terms of intra- and inter- patient variability following in vivo and ex vivo rFVIIa administration to haemophilia A and B patients with and without inhibitors. Patients ((3)16 years old) received the same intravenous rFVIIa dose (45, 90 or 180 microg/kg) twice, 1-12 weeks apart. Blood samples were collected pre-dose and 15, 60, 120 and 240 minutes post-dose for ROTEM and TEG analysis. Pre-dose samples were also spiked ex vivo with rFVIIa (0.6, 1.2 or 2.4 microg/ml), to correspond to the three in vivo doses. Twenty-six haemophilia A and four haemophilia B patients were enrolled. A significant treatment effect was observed with in vivo rFVIIa (p<0.05) with more pronounced effects in inhibitor (n=14) versus non-inhibitor (n=16) patients. There was a strong positive correlation between ROTEM and TEG parameters. Intra- and inter-patient variation was large for all thromboelastography parameters at all time points and rFVIIa doses. Intra-patient variation was generally lower for non-inhibitor than inhibitor patients, and lower following ex vivo spiking versus in vivo rFVIIa administration. In conclusion, there was a clear effect of rFVIIa on all thromboelastography parameters, but the large intra- and inter-patient variability following in vivo rFVIIa administration renders the use of our method unsuitable for dose-response prediction for haemophilia patients in the clinical setting.