To cite this article: Collins PW, Møss J, Knobe K, Groth A, Colberg T, Watson E. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost 2012; 10: 2305-12.Summary. Background: nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half-life. Objectives: To provide information on potential dose regimens for N9-GP for phase 3 pivotal and surgery trials. Methods: A population pharmacokinetic model was developed from single-dose data derived from the first human-dose trial with N9-GP in hemophilia B patients, and was used to extrapolate to steady-state conditions for different N9-GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9-GP with standard prophylactic regimens using rFIX or plasma-derived (pd) FIX (40 IU kg )1 every third day). Plasma activity following dosing with N9-GP, rFIX and pdFIX for surgery and on-demand treatment of bleeds was also simulated. Results: A linear twocompartmental model best described the pharmacokinetic profiles of N9-GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg )1 N9-GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL , respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL )1 for rFIX, and mean values of 43 and 2.1 IU dL )1 for pdFIX.Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9-GP vs. rFIX and pdFIX for surgery and the treatment of bleeds.Conclusions: N9-GP may allow prophylaxis, surgical dosing regimens and on-demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.
To cite this article: Møss J, Scharling B, Ezban M, Møller Sørensen T. Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects. J Thromb Haemost 2009; 7: 299-305.Summary. Background: NN1731 is a recombinant activated factor VII (rFVIIa) analog with enhanced activity. Objectives: This clinical trial aimed to assess the safety and pharmacokinetics of single doses of NN1731 in healthy male subjects. Methods: This was a randomized, placebo-controlled doseescalation trial with four dose tiers (NN1731 5-30 lg kg). Eight subjects were randomized to either NN1731 (n = 6) or placebo (n = 2) in each tier. Results: No thromboembolic or serious adverse events were reported and no antibody formation towards NN1731 was detected. NN1731 was demonstrated to be pharmacologically active based on coagulation-related parameters (prothrombin fragment 1+2, activated partial thromboplastin time and prothrombin time). There were five mild/moderate adverse events in three subjects. The FVIIa activity of NN1731 after ascending single-dose administration of NN1731 fits well with a two-compartment model, indicating a bi-exponential decline with a rapid initial distribution of approximately 73% FVIIa activity (half-life = 20 min), followed by a less rapid terminal elimination phase eliminating the remaining 27% (half-life = 3 h). Dose proportionality in healthy male subjects at the dose levels investigated (5-30 lg kg . No immunogenic or thromboembolic events were reported. The pharmacokinetic profile of NN1731 as measured by FVIIa activity appears to follow two-compartment pharmacokinetics characterized by an initial rapid distribution phase followed by a less rapid elimination phase.
To cite this article: Møss J, Rosholm A, Lauré n A. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost 2011; 9: 1368-74.Summary. Background: Extensive research is currently ongoing to prolong the half-life of coagulation factors. One of these techniques is glycoPEGylation, which has also been applied to recombinant activated factor VII (rFVIIa), resulting in a rFVIIa derivative (N7-GP) with a prolonged terminal half-life (t 1/2 ). The main clinical purpose of N7-GP is to provide safe and effective prophylaxis to patients with hemophilia and inhibitors. The prolonged t 1/2 of N7-GP can potentially reduce the dosing frequency and thereby facilitate convenience and compliance, which are two significant barriers to effective prophylaxis. Objectives: To determine the safety and pharmacokinetics of single doses of N7-GP in healthy men. Methods: A randomized, placebo-controlled, dose-escalation trial with five cohorts (N7-GP dose of 12.5-100 lg kg )1 ) was performed. In each cohort, eight subjects were randomized to receive N7-GP (n = 6) or placebo (n = 2). Results: The mean FVIIa activity was measurable for up to at least 72 h after dosing, and the overall mean t 1/2 for FVIIa activity was 15 h. The pharmacokinetics of N7-GP appeared to be dose-proportional in the dose range investigated. No serious adverse events (including thromboembolic events) were reported. The frequency of adverse events was similar in both the placebo and N7-GP groups. No neutralizing antibodies against N7-GP were detected. A pharmacologic effect was apparent from a dose-dependent statistically significant decrease in the mean prothrombin time in all N7-GP groups as compared with placebo. Conclusions: N7-GP had a plasma half-life of 15 h and a profile that makes it a potential candidate for prophylaxis in patients with hemophilia and inhibitors.
Summary. Background: Turoctocog alfa (NovoEight â ) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. Objectives: To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Patients/methods: Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg À1 dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Results: Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t 1/2 tended to increase with increasing age, with lower AUC and shorter t 1/2 being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. Conclusions: The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products.
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