ABSTRACT
INTRODUCTION: Bleeding episodes in haemophilia patients with inhibitors are primarily treated with by-passing agents such as recombinant activated FVII (rFVIIa). Prophylactic treatment with rFVIIa has been shown to significantly reduce the number of bleeding episodes as compared to conventional on-demand haemostatic therapy, and a reduced dosing frequency could present an improved treatment option in inhibitor patients. MATERIALS AND METHODS: A series of glycoPEGylated rFVIIa derivatives (5-40K PEG) has been produced and their effect and pharmocokinetics have been investigated in several animal species. RESULTS: The glycoPEGylated rFVIIa derivatives exhibit significant prolongation of half-life in mice, dogs and pigs as measured by rFVIIa clot activity. The clearance of rFVIIa, rFVIIa-5K PEG, rFVIIa-10K PEG, rFVIIa-20K PEG and rFVIIa-40K PEG in minipigs were estimated to 59, 27, 22, 8.7 and 3.1 ml/h/kg, respectively. Across species a reduction in clearance as a function of the size of the attached PEG was observed. By allometric scaling, the compiled pharmacokinetics predicts a human half-life for rFVIIa-10K PEG and rFVIIa-40K PEG of approximately 7 and 12h, respectively. The rFVIIa-10K PEG and rFVIIa-40K PEG are efficacious in stopping a bleed in the haemophilia A mouse tail-bleeding model after intravenous administration. CONCLUSIONS: GlycoPEGylation of rFVIIa significantly increases the rFVIIa exposure in three animal models, glycoPEGylated rFVIIa compounds are effective in vivo and thus, represents a potential prophylactic treatment option for patients with inhibitors.
Subject(s)
Factor VIIa/pharmacokinetics , Hemophilia A/metabolism , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Animals , Disease Models, Animal , Dogs , Factor VIIa/chemistry , Factor VIIa/pharmacology , Female , Glycosylation , Half-Life , Hemorrhage/etiology , Hemorrhage/metabolism , Humans , Male , Mice , Polyethylene Glycols/pharmacology , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/pharmacology , Swine , Swine, Miniature , Tail/blood supplyABSTRACT
BACKGROUND: Recombinant human GH (rhGH) is usually administered as a daily sc injection, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed with the aim of reducing serum clearance and thereby prolonging the exposure leading to once-weekly sc administration. OBJECTIVES: In this first human dose trial, the safety, tolerability, pharmacokinetics, and pharmacodynamic parameters of a single administration of NNC126-0083 were evaluated. SUBJECTS AND METHODS: Seven groups of eight healthy male volunteers were dosed once with a single sc administration of NNC126-0083 (n = 6) or placebo (n = 2). The doses were escalated between the cohorts in a sequential mode. Blood samples for assessment of safety, pharmacokinetics, and pharmacodynamic response (IGF-I, IGF binding protein-3, free IGF-I) as well as GH binding protein were taken up to 240 h after dosing. RESULTS: Seven doses of NNC126-0083 were administered. After NNC126-0083 administration, a significant deviation from pharmacokinetic dose proportionality was observed for the highest doses. A strong dose-dependent pharmacodynamic response was seen with elevated levels of IGF-I and IGF binding protein-3 for all doses administered. The elevation was maintained for more than 1 wk for the highest doses. All doses of NNC126-0083 were well tolerated. No local tolerability issues were identified. CONCLUSION: After a single sc administration of NNC126-0083 in healthy male volunteers, a sustained dose-dependent pharmacodynamic response was induced. These results indicate that NNC126-0083 has the potential for an efficacious, well-tolerated, once-weekly rhGH compound in the treatment of GH deficiency in adults.
