Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs.
The objective of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new recombinant FVIII compound turoctocog alfa and a Glyco-PEGylated FVIII derivative thereof (N8-GP) in Haemophilia A dogs. Six haemophilic dogs divided into two groups were included in the study. Each dog was administered a dose of 125 U kg(-1) , blood samples were collected at predetermined time points for both pharmacokinetic (FVIII measured by one-stage aPTT assay) and pharmacodynamic [whole blood clotting time (WBCT)] evaluations. After intravenous administration to haemophilic dogs, the plasma concentration at the first sampling point was comparable for turoctocog alfa and N8-GP, and the clearance was estimated to be 6.5 and 3.9 mL h(-1) kg(-1) for turoctocog alfa and N8-GP respectively. Both turoctocog alfa and N8-GP were able to reduce the WBCT time to normal levels (<20 min), however, the reduced clearance was reflected in the WBCT, which returned to baseline at a later time point for N8-GP as compared with dogs dosed with turoctocog alfa. The clearance was 40% reduced for N8-GP as compared with turoctocog alfa. Simulations of a multiple dosing regimen in dogs, suggest that to maintain WBCT <20 min N8-GP can be dosed at reduced intervals, e.g. with 4 days between doses, whereas turoctocog alfa will have to be dosed with 2½ day between doses. Data thereby supports N8-GP as an alternative to standard rFVIII replacement therapy, with a more convenient dosing regimen.
Biopharm Research Unit, Novo Nordisk A/S, Maaloev, Denmark. hkag@novonordisk.com
H
H
Agersø
H R
HR
Stennicke
H
H
Pelzer
E N
EN
Olsen
E P
EP
Merricks
N A
NA
Defriess
T C
TC
Nichols
M
M
Ezban
D000818:Animals; D004285:Dogs; D005169:Factor VIII / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy*; D008297:Male; D010314:Partial Thromboplastin Time; D011092:Polyethylene Glycols / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013916:Thrombelastography; D014914:Whole Blood Coagulation Time
C579325:N8-GP compound; C577506:recombinant factor VIII N8; D011092:Polyethylene Glycols; D005169:Factor VIII