تنظیم مراحل برای درمان شخصی بیماری هموفیلی: نقشی فارماکوکینتیک Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?

1. Hemophilia and current treatment 1.1. Background of the disease Hemophilia A and B are X-linked inherited bleeding disorders characterized by deficiencies of factor VIII (FVIII) and factor IX (FIX), respectively. Prevalence is estimated at 1 in 5000 male births for hemophilia A and 1 in 30,000 male births for hemophilia B [1,2]. FVIII and FIX enhance formation of thrombin and consequently stabilize the hemostatic clot by increased fibrin formation. Disease severity is classified according to residual FVIII or FIX coagulation activity in plasma [3]. Mild hemophilia patients have FVIII or FIX levels of 0.05–0.40 IU mL−1 , moderate patients FVIII or FIX levels of 0.01–0.05 IU mL−1 and severe patients FVIII or FIX levels of < 0.01 IU mL−1 . Mild hemophilia is characterized by an increased risk of bleeding after trauma or surgery. Moreover, severe as well as moderate hemophilia patients suffer from spontaneous bleeding or bleeding after minimal trauma in muscles and/or joints, potentially resulting in disabling arthropathy [4]. Strikingly, bleeding phenotype differs between hemophilia patients with identical baseline FVIII or FIX levels and is probably influenced by inter-individual variation in patient characteristics such as age, body weight, modifying factors within the hemostatic system, behavioral factors and daily (sporting) activities and other yet unidentified factors [5–10]. In addition, it may be influenced by interindividual variation of half-life of clotting factor concentrates (CFC) administered either prophylactically or on demand (Table 1). 1.2. Current treatment with replacement therapy Replacement therapy with CFC can be given to prevent spontaneous or repetitive bleeding (prophylaxis), or “on demand” to treat acute bleeding and prevent bleeding at the time of dental or surgical procedures. Current CFCs are either of recombinant or plasma-derived origin. Prophylaxis is the mainstay of treatment in hemophilia. Its introduction has dramatically changed the lives of many hemophilia patients. Consequently, hemophilia has evolved from a crippling disease with a shortened life expectancy into a disease with a normal life expectancy, significantly less joint arthropathy and acceptable quality of life [11,12]. 1.2.1. Prophylaxis Prophylaxis was introduced in 1965 by Ahlberg and is based on the observation that moderate hemophilia patients with FVIII or FIX levels above 0.01 IU mL−1 have far fewer joint bleeds and less subsequent arthropathy [13]. Therefore, it was reasoned that joint bleedings could be prevented in severe hemophilia by keeping FVIII and FIX levels above 0.01 IU mL−1 . To achieve this, CFCs must be regularly infused generally two to four times a week in hemophilia A and one to three times a week in hemophilia B [14–17]. Prophylactic treatment profoundly reduces frequency of bleeding and improves joint status as demonstrated by Manco Johnson et al. in a randomized controlled trial [11]. Various guidelines for prophylaxis are available of which Table 2 shows a selection of those most often applied. The efficacy of prophylaxis in preventing joint bleedings is largely dependent on maintaining minimal FVIII and FIX trough levels of 0.01 IU mL−1 in the patient. Moreover, time spent below trough levels is associated with number of bleeding events [18]. However, in standard clinical practice, trough levels are rarely measured and dose and frequency of prophylactic infusions are only adjusted when spontaneous or frequent bleeding occurs.