C was raised from 0.89 (SD 0.73) U dL(-1) during standard dosage to 2.2 (1.5) U dL(-1) during pharmacokinetic dosage. Concomitantly, mean 6-month consumption of factor VIII was decreased from 124 000 (SD 30 000) units to 84 000 (31 000) units. Numbers of reported bleedings were generally similar during both periods. The study demonstrates the usefulness of individual pharmacokinetics as a tool for cost-effective utilization of factor VIII in the prophylactic treatment of haemophilia A.
This article reviews the pharmacokinetics of exogenous factor VIII and factor IX in patients with haemophilia. It focuses on the methodology (and inherent pitfalls) of pharmacokinetic studies, then summarizes available pharmacokinetic data and finally discusses some applications of pharmacokinetics for optimization of prophylactic treatment of haemophilia and for comparison of coagulation factor concentrates.
The aim of this study was to investigate the use of single-dose pharmacokinetic data for factor IX (FIX) to predict multidose pharmacokinetics and explore their use for pharmacokinetic dosing in prophylactic treatment of haemophilia B. Eight patients with severe haemophilia B were enrolled. Using single-dose pharmacokinetic data for each patient, plasma factor IX procoagulant activity (FIX:C) curves during prophylactic dosing were computer-simulated. The simulations were verified by repeated blood sampling and measurements of FIX:C. Theoretical dosing regimens to maintain a plasma trough level of 1.0 U dL-1 of FIX:C were calculated. A 2 x 2 week cross-over study on standard dosing according to bodyweight vs. dosing every three days based on individual pharmacokinetics was carried out. FIX:C was measured during each treatment period. FIX:C data from the plasma sampling generally confirmed the single-dose pharmacokinetic data used. Pharmacokinetically tailored dosing of FIX could result in considerable savings of factor concentrate as compared to current standard dosing. The study demonstrates the applicability of individual pharmacokinetics as a tool for cost-effective utilization of FIX concentrates in the prophylactic treatment of haemophilia B.
SummaryThe purified factor IX concentrates Nanotiv (Kabi Pharmacia), Immunine (Immuno), Factor IX VHP (Bio-transfusion), Alphanine (Alpha) and Mononine (Armour) have been studied in vitro and compared with the prothrombin complex concentrates (PCCs) Preconativ (Kabi Pharmacia) and Prothromplex TIM4 (Immuno). The measured values for factor IX coagulant activity (IX: C) were in good agreement with the manufacturer’s label values. In contrast to the PCCs, most of the purified concentrates were virtually devoid of other vitamin K-dependent coagulation factors, the inhibitors protein C and S as well as fibrinogen, fibronectin and immunoglobulins. Indicators of thrombin generation, namely prothrombin fragments 1 and 2 (F 1 + 2) and thrombin-antithrombin complex (TAT), were present in varying amounts in all preparations. The specific activity in the purified concentrates exceeded that in the PCCs by a factor of 50-100. Some differences in purity were found between the purified concentrates.In vivo, Nanotiv was compared with Preconativ and Immunine with Prothromplex TIM4 in crossover studies in patients with severe hemophilia B, and Mononine was tested in a single drug study. Most of the preparations yielded postinfusion increases in TAT, but not in FI + 2. Pharmacokinetic variables were analyzed with non-linear curve-fitting combined with model-independent methods. In retrospective comparisons, there were no apparent differences between Nanotiv, Preconativ and Mononine, whereas in vivo recovery seemed lower and the apparent clearance higher for Immunine and Prothromplex. Purified factor IX concentrates were successfully used as cover for surgery or in immune tolerance induction.
The aim of this study was to investigate individual pharmacokinetics as a tool for dosing of factor VIII (FVIII) in severe hemophilia A. It is assumed that effective prophylaxis against bleedings is maintained if the plasma FVIII:C activity is kept above 1 U/dl, and the present study is based on this assumption. A current standard dosage regimen for FVIII is 25–40 U/kg up to three times weekly. However, there is considerable individual variation in the pharmacokinetics of FVIII:C. Individual pharmacokinetic data were used to computer‐simulate plasma activity curves after repeated doses in 8 patients. Going from prophylaxis regimens of normally 2–3 infusions per week to dosing every 2 days would theoretically reduce their average FVIII consumption by 43% with maintained or increased trough levels of FVIII:C. Daily dosing would reduce their mean FVIII usage by 82%. Modified dosage regimens, infusions every 2 days, were implemented in the patients, and plasma samples were drawn to verify the pharmacokinetic models. The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed. Dosing of coagulation factors according to kinetic principles can result in more cost‐effective utilization of these very expensive preparations.
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