Pharmacokinetics can be defined simply as the processes which govern drug concentrations and clearly these have to be understood in order to know what is happening when we treat patients. It was therefore timely to bring together a group of international experts under the chairmanship of Manuel Carcao and Erik Berntorp in Toronto, a ‘meeting place’ in the Huron (native) language – a meeting of rivers where historically people traded goods. Together these experts from Canada, Sweden, Germany, China, the USA, Italy and the UK explored pharmacokinetics, patient variability and pharmacoeconomics across different healthcare systems. The relevance of these discussions are against the setting of the availability of more concentrates; improved production technology and viral attenuating procedures which raise questions regarding efficacy (recombinant factor IX (rFIX), BDD recombinant factor VIII (rFVIII)); and new treatment programmes including prophylaxis and inhibitor treatment. The papers included in this report are the contributions from the respective experts at this meeting. An unrestricted educational grant from Bayer Biologics and Bayer Canada has made the publication of this supplement possible. Massimo Morfini, the doyen of pharmacokinetics as applied to haemophilia, discusses the conduct of a good pharmacokinetic study introducing his talk with the quotation from British scientist Lord Kelvin: ‘when you can measure what you are speaking about and express it in numbers you know something about it: but when you cannot measure it, your knowledge is of meagre and unsatisfactory kind.’ The prerequisites for a good pharmacokinetic study are summarized by having a good quality clinical trial; precise, accurate and sensitive assays; and using all relevant data. There is an experience in Sweden of therapeutic drug monitoring based on pharmacokinetics which extends back for 50 years. Sven Björkman shares this experience and explains how pharmacokinetic studies are needed for both concentrate standardization (in vivo recovery and half-life and cross-over comparison of a new and established concentrate) and therapy (therapeutic drug monitoring and the calculation of the dose required for a specific coagulation factor level). The limited half-life of factor FVIII (FVIII) has always been a challenge for in vivo dosing and this has stimulated the search for a protein with longer half-life using the techniques of molecular engineering. Eugueni Saenko discusses the ongoing work of introducing mutations into the FVIII molecule to increase the half-life. Postinfusion plasma measurements are essential in the assessment of new products, where there is a change in site or process of manufacture and as a surrogate for haemostatic effect. Trevor Barrowcliffe reviews the difficulties that have been encountered using the one-stage and chromogenic assays. We are reminded that the recent interest in global haemostasis using thrombin generation is exploiting methodology developed in 1953 by Biggs and Macfarlane. Effective prophylaxis is most important in children with haemophilia and there are special considerations to drug dosing in children. These are confidently expounded by Paul Pencharz who concludes that factor concentrates are proteins and thus in the face of the high metabolic rate in children they will be cleared more quickly. Victor Blanchette reminds us of a quotation from Abraham Jacobi ‘Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but … has its own independent range and horizon’: there are many unanswered questions reflecting the paucity of data in a difficult to study population and the variable dosing based on body weight, lean body mass, surface area or liver weight. Chris Barnes and Manuel Carcao present the results of a study of 20 boys with severe or moderate haemophilia A undergoing a pharmacokinetic study of their handling of FVIII (Kogenate-FS®) and based on their results suggest a number of intrapatient variables that may correlate with their handling of factor concentrates. They also explain the difficulties of attaining pharmacokinetic data in children not least because of limitations imposed by research ethics boards. For these reasons the use of population pharmacokinetic analysis is explored for paediatric patients by Heino Stass. In this way a minimal sampling schedule can be established for children. Pharmacokinetic analysis is intrinsic for both the diagnosis and management of inhibitors. Donna DiMichele discusses the impact of low titre inhibitors and non-neutralizing anti-FVIII antibodies on pharmacokinetics as well as the use of these parameters to define successful IT outcome. Well-designed pharmacokinetic studies are advocated in haemophilic children of all ages and ‘the question of ethics should not be there’. Inevitably more focus is made to FVIII deficiency but Man-Chiu Poon presents data on the pharmacokinetics of factor IX (FIX), recombinant factor VIIa (rFVIIa) and factor XIII (FXIII) used to treat more rare coagulation deficiencies. The pharmacokinetics of FIX has always presented a challenge because of the rapid reversible binding to vascular endothelium which seems exacerbated for rFIX. This of course has enormous economic implications. The pharmacokinetics of rFVIIa are variable according to use in children, adults, in patients with inhibitors or in FVII-deficient patients. The very short half-life of rFVIIa means that a clear understanding of its pharmacokinetics is paramount for dosing effectively in these different situations. The pharmacokinetics of FXIII is important for treatment of FXIII deficiency which although rare in Europe at one per million occurs commonly in those parts of the world where consanguineous marriages are more common. Erik Bertorp reminds us that ‘PK-thinking’ is not a new entity. The contributions made in 1976 by Schimpf, Morfini and Aronstam should not be forgotten. The Swedish group have further refined these ideas and used computer modelling to calculate individualized theoretical dosing regimens calculated to maintain a trough level of 1% exogenous FVIII for prophylaxis. The papers contained in this supplement are written by the participants of this stimulating symposium entitled Pharmacokinetics of factor concentrates in haemophilia – challenges and relevance to clinical practice. It is clear that the pharmacokinetics of FVIII, FIX, rFVIIa and FXIII have been extensively investigated enabling therapeutic plasma levels to be defined in most situations. Applications of these principles will not only result in effective treatment but also cost-effective treatment. Unfortunately constraint of the vial size and the need to deliver treatment by the intravenous route limits the application of these pharmacokinetic principles – these are challenges for the future.
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C.A. Lee (2006) studied this question.