Individualized prophylaxis for optimizing hemophilia care: can we apply this to both developed and developing nations?

Abstract

Prophylaxis is considered optimal care for hemophilia patients to prevent bleeding and to preserve joint function thereby improving quality of life (QoL). The evidence for prophylaxis is irrefutable and is the standard of care in developed nations. Prophylaxis can be further individualized to improve outcomes and cost effectiveness. Individualization is best accomplished taking into account the bleeding phenotype, physical activity/lifestyle, joint status, and pharmacokinetic handling of specific clotting factor concentrates, all of which vary among individuals. Patient acceptance should also be considered. Assessment tools (e.g. joint status imaging and function studies/scores, QoL) for determining and monitoring risk factors and outcome, as well as population PK profiling have been developed to assist the individualization process. The determinants of optimal prophylaxis include (1) factor dose/dosing frequency, hence, cost/affordability (2) bleeding triggers (physical activity/lifestyle, chronic arthropathy and synovitis) and (3) bleeding rates. Altering one determinant results in adjustment of the other two. Thus, the trough level to protect from spontaneous bleeding can be increased in patients who have greater bleeding risks; and prophylaxis to achieve zero joint bleeds is achievable through optimal individualization. Prophylaxis in economically constrained nations is limited by the ill-affordability of clotting factor concentrates. However, at least 5 studies on children and adults from Thailand, China and India have shown superiority of low dose (~5-10 IU kg^-1 2-3× per week) prophylaxis over episodic treatment in terms of bleed reduction, and quality of life, with improved physical activity, independent functioning, school attendance and community participation. In these nations, the prophylaxis goals should be for improved QoL rather than "zero bleeds" and perfect joints. Prophylaxis can still be individualized to affordability. Higher protective trough level can be achieved by using smaller doses given more frequently without an increase in consumption/cost. The bleeding trigger can also be down-regulated by avoiding unnecessary injury, and by engaging in judicious strengthening exercises appropriate to the joint status to improve balance and joint stabilization. Central to the success of prophylaxis are clinics with comprehensive care that provide the necessary professional expertise, support, and counseling, to educate patients, families, and other healthcare professionals, and to support research for improved hemophilia care.

Keywords: Hemophilia; Individualized prophylaxis; Low-dose prophylaxis; Personalized prophylaxis; Pharmacokinetics; Population pharmacokinetics; Terminal half-life.

Fig. 1

Determinants of prophylaxis. Prophylaxis treatment regimen has 3 main determinants: (1) the given resources/concentrate availability/afffordability to target a specific trough level and/or dosage/intervals of infusions, all of which reflect the consumptions/costs; (2) the bleeding trigger, which comprises physical activity/lifestyle, presence and degree of arthropathy, and presence of chronic synovitis; and (3) the number of bleeds, especially joint bleeds, that are regarded as acceptable. These 3 determinants form a triangle. If 1 determinant is changed, the other 2 will adjust. Central to these, patient acceptability and ability to self-guided care must also be considered. With unlimited resources, “zero bleeds” and normal physical activity may be targeted. With few resources, only low-dose substitutions may be given, thus accepting a certain number of bleeds and limited physical activity. None-the-less where acceptable to the patient with adequate venous access, increasing frequency of infusion will attain a higher trough level with a lower dose (and hence consumptions/costs, see Fig. 2). Determinant 2 can also be improved by avoiding injury and by improving muscle strength and balance with exercise appropriate to the patients’ joint status. (Adapted from Oldenburg [17], with permission)

Fig. 2

Low dose prophylaxis in economically constrained environment: Influence of FVIII infusion frequency on trough level and factor consumption. (Modeled based on an average FVIII recovery of 2 IU dL⁻¹ per IU kg⁻¹ infused and a T_1/2 of 12 h). a A dosage of 10 IU kg⁻¹ two-times a week as well as 5 IU kg⁻¹ three-times a week (weekly consumption 20 and 15 IU kg⁻¹ per week respectively) each results in a trough level <1 IU dL⁻¹ in 3–4 of the 7 days in the week (but with trough levels always higher with three-times a week than with two-times a week prophylaxis even at lower dose with lower consumption), whereas as little as 2 IU kg⁻¹ daily (qd, weekly consumption 14 IU kg⁻¹ per week) produces daily trough of ~1.33 IU dL⁻¹. [For three-times weekly prophylaxis, doubling the infusion dose from 5 to 10 IU kg⁻¹ will double the day 2, 4 and 6 trough levels to ~1.33 IU dL⁻¹, but still leave trough level on day 7 at 0.66 IU dL⁻¹ (i.e. <1 IU dL⁻¹, figure not shown)]. Prophylaxis at 10 IU kg⁻¹ every-two-day (q2d) is shown in Fig. 2b. b In order for an every-three-day (q3d) regimen to produce a trough level similar to that obtained by every-two-day (q2d) infusion (e.g.1.33 IU/dL), the dosage per infusion has to be increased, whereas daily infusion requires a lower per infusion dosage. Compared to the q2d regimen, factor consumption is 2.8× more for the q3d regimen but 2.5× less for the qd regimen. These relative consumption multiples are the same for other target trough levels and other PK handling of clotting factors for a particular individual. (Figures not drawn to scale. Peak and trough levels will be different for different patients depending on their individual pharmacokinetic handling of the particular clotting factor, but the principles remain the same. Peak and trough levels tend to increase slightly with infusions but remain more or less constant after the first few infusions and steady state is achieved. Values for peak levels represent value range during steady state with each regimen)