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• W1946756211 abstract "Pharmacokinetic (PK) evaluation of clotting factor concentrates has since 1988 been a recommended procedure to evaluate not only the bioequivalence of new and older products but also to tailor replacement therapy in patients with inherited clotting factor deficiency [1]. Pharmacokinetics of Factor VIII/IX concentrates are quite easy to be assessed in haemophilia patients. Severe Haemophilia A/B patients are supposed to be a quite homogeneous population and the factor VIII/IX genotypes seem to play a moderate role in pharmacokinetic characteristics of rDNA- or plasma-derived concentrates. The conditions are completely different and much more complex when the behaviour of von Willebrand factor (VWF) concentrates in von Willebrand’s disease (VWD) patients must be characterized. In this case, we have to take into account several sources of variability: The heterogeneity of patients: only type 3 or severe type 1 should be considered in the conduction of single dose PK studies as types 2A or 2M behave differently. Only a few studies have been conducted in type 3 VWD homogeneous cohorts [2, 3]. The VWF/FVIII ratio is very different in the final formulation of VWF concentrates: Intermediate Purity Concentrates (IPC) are rich of high molecular weight multimers of VWF and have a ratio 2.0–2.5 whilst High Purity Concentrates (HPC) have a ratio 1.0–1.2. Furthermore, a pure VWF concentrate which does not contain FVIII is also available. VWF:Ag, VWFR:Co, VWF:CBA should be dosed to have a complete picture of protein decay. Such accurate evaluation of VWF has been conducted in only one study [4]. FVIII:C decay is very hard to evaluate because the plasma concentration is the sum of administered and endogenously synthesized FVIII. After infusion of IPC an increase or a plateau of FVIII concentration can be observed, during the first 12–24 h. This phenomenon sometimes makes it impossible to use the standard PK analysis, both by non-compartment and compartment methods, because when the FVIII is increasing the Clearance becomes negative and only terminal half life can be evaluated. This is the reason why in most studies evaluating the PK of IPC, FVIII kinetics has been omitted [2, 3, 5, 6]. After infusion of pure VWF concentrate, the FVIII increase is due exclusively to the endogenous synthesis of FVIII and it is difficult to define its decay [3, 7], except when the timing of blood collection is prolonged up to 96 h [8]. The different ratio VWF:RCo/FVIII is a confounding factor in the dosing of PK procedures. During PK studies, each dose must be entered in terms of plasma concentrations of the factor under investigation, as recently pointed out by Kessler and colleagues [9]. The gold rule of PK for good analysis is that the pre-infusion baseline concentration must be achieved at the end of the decay curve. In some studies the blood sample collection have been truncated at 24 h [2, 4] or at 48–50 h [5, 6] when still the trough was quite high. In only two studies were the blood samples collected up to at 72 h [7, 9] or 96 h [3, 8]. This discrepancy of study design does not allow a direct comparison among the different concentrates. For the best definition of a decay of a clotting factor concentrate at least three parameters must be reported: Clearance, Volume of distribution Area (VdArea), preferably normalized for body weight (expressed as ml/h/kg or ml/kg, respectively), and Mean Residence Time (MRT). Also Terminal half life can be useful if the fitting of the last 3 o 4 points is linear. Unfortunately, very frequently only In Vivo Recovery (IVR) has been mentioned but it is well known how this parameter is misleading because it is derived from a single point. As a minimum, the peak during the first hour should be considered. As recently pointed out, the IVR does not correlate with haemostatic efficacy [10]. More reliable is the VdArea, which is similar to IVR but is derived from all decay curve and for this reason is not affected by variability of the first hour levels. A further controversial issue, is how to define the dosage in the replacement therapy of vWD patients: VWF:RCo or FVIII? As recently pointed out [11] the two aims of treatment of bleeding episodes of VWD patients are: (i) the correction of the abnormal platelet adhesion due to reduced and/or dysfunctional VWF, and (ii) the increase of the reduced level of Factor VIII:C. Both these aims are essential requirements of the first line therapy for prevention of surgical bleeding and for the treatment of spontaneous bleeding episodes. The information about the labelled potency of each concentrate in terms of VWF:RCo and FVIII:C should be known to the physicians in selecting the most suitable replacement product. According to the guidelines of Italian Association of Haemophilia Centers (AICE) [12] the treatment should be dosed in terms of VWF:RCo and this is also the recommendation of the NHLBI Belgian and Dutch guidelines and in the Wilate and Alphanate package inserts. The article by Raquet and colleagues in this issue of Haemophilia tried to address some of the difficulties of VWF kinetics, the different FVIII behaviours after repeated and equal VWF:RCo doses of concentrates with different VWF:RCo/FVIII ratio, IPC and HPC. The normal rabbit animal model used by the authors does not take into account the endogenous synthesis of VWF. This model can make easier the estimation of FVIII decay without any in vivo interference but the outcome of treatment in VWD patients is quite different. Furthermore, in contrast to the single dose PK study, the FVIII decay was evaluated at the end of repeated infusions. It is evident and easily understandable that IPC (higher VWF:RCo/FVIII ratio) is able to achieve a lower FVIII concentration than HPC (lower VWF:RCo/FVIII ratio) if the loading and maintenance doses have been tailored according to VWF:RCo content of the final formulation of each concentrate. It is also evident that AUC of IPC is lower than that of HPC but comparing the last loading dose with the AUC, i.e. taking into account the amount of plasma made free of concentrate, the Clearance, the IPC showed a longer permanence of FVIII in the blood stream, i.e. smaller Clearance than HPC. Similar findings have been published recently [9]: the Cmax of FVIII after infusion of the same VWF:RCo dose of IPC and HPC were higher for HPC whilst the terminal half lives were similar. When the FVIII Clearance was evaluated according to the FVIII dose administered, the HPC showed a faster Clearance, about the double that of IPC. This finding might question the declared bioequivalence of the two concentrates, as claimed in the article [9]. The difference of FVIII Clearance in the article of Raquet and colleagues cannot be explained by the different half life of VWF:Ag, even though the timing is too short (10 h) and the baseline too high to allow a correct kinetics analysis. A well designed crossover PK study comparing IPC against HPC, head-to-head, taking into account Clearance, MRT and VdArea contemporary, has never been done. In one of the two cross-over studies published so far [2, 9], PK analysis was not done [2] and in the other [9] the most important PK parameter, the Clearance (the only one describing how AUC is related to the dose given), has not been properly considered. There is only evidence from different studies that in patients with VWD, a sustained FVIII increase, up to a plateau for the first 12–24 h, has been achieved only after infusion of IPC [5, 6, 9]. Instead, after the infusion of HPC the decay is steeper, according to a bi-exponential curve [4, 9]. Furthermore, the decay of VWF:RCo of all concentrates is always faster than that of VWF:Ag, indicating a more rapid decrease of the functional properties of the protein [2, 5-8]. The complex in vivo behaviour of FVIII:C after infusion of IPC has been known since the first study [6]. Only a mathematical procedure, more complex than standard PK methods, taking into account the fall off of FVIII:C after the initial phase of increase or plateau, can approach the correct pharmacokinetics of FVIII:C in VWD patients. The timing of this kind of PK studies should be prolonged to least up to 96 h [13]. At present, only careful monitoring of FVIII:C plasma concentrations can avoid over- or under-treatments of VWD patients. The author stated that he had no interests which might be perceived as posing a conflict or bias." @default.
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• W1946756211 date "2011-10-26" @default.
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• W1946756211 title "Pharmacokinetics of VWF/FVIII concentrates is a very intricate matter" @default.
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• W1946756211 doi "https://doi.org/10.1111/j.1365-2516.2011.02663.x" @default.
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