Comparative pharmacokinetic studies in haemophilia

The general rules of pharmacokinetics have been applied to the study of the behaviour of clotting factor concentrates in patients with haemophilia. Since 1980, the continuous development of innovative plasma- and rDNA-derived concentrates and the implementation of new virucidal methods in manufacturing processes has prompted us to define a standard approach to this issue. Model-based methods, based upon one or two open compartment models, were available when this work was initiated. Unfortunately, these methods are supported by very little biological data and are profoundly affected by the goodness-of-fit of the data. In contrast, the model-independent method, which is not affected by errors in fitting, provides reproducible and reliable estimates of the behaviour of clotting factor concentrates in patients with haemophilia. Further, the calculations required for the model-independent method are quite simple and can be computed using a pocket minicomputer. The need for an accurate standardization has been recognized by the Factor VIII/IX Sub-Committee which, in 1991, issued the first recommendations on the pharmacokinetic evaluation of Factor VIII/IX concentrates. A recent revision of the recommendations has been made available on the web site of the International Society on Thrombosis and Haemostasis. The most crucial changes - sample size, study design, dosages in single-dose studies, potency assessment, need for well-defined standards, optimal number of points, and most important outcomes - are discussed in this report. In addition, the model-independent and compartmental methods are described.