Population pharmacokinetic modelling of fibrinogen in patients with congenital or acquired-chronic or acute-hypofibrinogenaemia

AimsFibrinogen is the key substrate for coagulation. Fibrinogen pharmacokinetics (PK) after single doses of fibrinogen concentrate (FC), using modelling approaches, has only been evaluated in congenital afibrinogenaemic patients. The aims of this study are to characterize the fibrinogen PK in patients with acquired-chronic (cirrhosis) or acute-hypofibrinogenaemia (critical haemorrhage), showing endogenous production. Influencing factors of differences on the fibrinogen PK between subpopulations will be identified. MethodsA total of 428 time-concentration values from 132 patients were recorded. Eighty-two out of 428 values were from 41 cirrhotic patients administered with placebo and 90 out of 428 were from 45 cirrhotic patients that were given FC, 161 out of 428 values were from 14 afibrinogenaemic patients and 95 out of 428 values were from 32 severe acute trauma haemorrhagic patients. A turnover model that accounted for endogenous production and exogenous dose was fitted using NONMEM74. The production rate (Ksyn), distribution volume (V), plasma clearance (CL) and concentration yielding to 50% of maximal fibrinogen production (EC50) were estimated. ResultsFibrinogen disposition was described by a one-compartment model with CL and V values of 0.0456 L center dot h(-1) and 4.34 L center dot 70 kg(-1), respectively. Body weight was statistically significant in V. Three different Ksyn values were identified that increased from 0.00439 g center dot h(-1) (afibrinogenaemia), to 0.0768 g center dot h(-1) (cirrhotics) and 0.1160 g center dot h(-1) (acute severe trauma). EC50 was of 0.460 g center dot L-1. ConclusionsThis model will be key as a support tool for dose calculation to achieve specified target fibrinogen concentrations, in each of the studied populations.