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Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8 ‐ GP in haemophilia A dogs

2012; Wiley; Volume: 18; Issue: 6 Linguagem: Inglês

10.1111/j.1365-2516.2012.02896.x

1365-2516

Henrik Agersø, H.R. Stennicke, H. Pelzer, E. N. Olsen, Elizabeth P. Merricks, Natalie DeFriess, Timothy C. Nichols, Mirella Ezban,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Summary 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.