Subsequently pharmacokinetic data on INCB024360 FVIII from 147 individuals with haemophilia A (48 children ages 1–6 years

of age and 99 individuals ages 10–65 years of age) were used for simulations of commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis [30]. The results of the simulations demonstrated that individual half-life of infused FVIII and frequency of dosing have a much larger effect on FVIII trough levels and time per week with FVIII levels <1% than recovery and infused dose. Given the significant variation of individual patients’ FVIII and FIX pharmacokinetic profiles, attention to frequency of infusions should allow a more cost-effective use of FVIII and FIX in prophylaxis regimens. The concept that pharmacokinetically tailored dosing of FVIII and FIX could result in considerable savings of factor concentrates compared to standard

(‘fixed’) prophylaxis protocols is supported by publications of Carlsson, Björkman, Berntorp and co-workers [30–33]. A challenge to PK directed therapy that would allow easy alteration in prophylaxis regimens to achieve, for example, higher threshold (‘trough’) FVIII or FIX levels, is the perceived need to perform very demanding conventional PK studies on individual patients. This problem can be overcome buy Trametinib by using Bayesian PK analysis, utilizing a population pharmacokinetic model that allows a sparse blood sampling protocol [34]. Use of prophylaxis in the late adolescent/adult haemophilia population is increasing particularly in countries with unrestricted access to safe FVIII and FIX concentrates [35,36]. As an

example in a recent survey of 2663 persons with haemophilia A or B followed in Canadian 上海皓元 Comprehensive Care Hemophilia Treatment Centres, 53% of individuals with severe haemophilia A and 20% with severe haemophilia B >18 years of age were identified to be receiving prophylaxis defined as the infusion of FVIII or FIX at least once weekly for >45 weeks during the year 2006 [37]. An important question, in the context of prophylaxis use in the adult haemophilia population, is whether prophylaxis can be safely discontinued in individuals who have been receiving intermediate or full-dose prophylaxis from an early age of life. Data reported from Denmark and the Netherlands are instructive in this regard. In Denmark, patients with severe haemophilia are treated using the high-dose Swedish prophylaxis protocol, whereas the Dutch patients, as described earlier in this review, receive an intermediate-dose prophylaxis regimen. Of a total 49 Dutch patients who received intermediate-dose prophylaxis from an early age in life, 11 (22%) were able to permanently discontinue prophylaxis [38]. The median age of the cohort was 23.4 years at the time of analysis, and the median follow-up off prophylaxis was 3.2 years.