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Personalising management of severe haemophilia A

Here we discuss how knowledge of pharmacokinetics is increasingly impacting and personalising the management of haemophilia A
Paul Batty MBBS BSc(Hons) MRCP(UK) 
Blizard Institute of Cell and
Molecular Science,
Queen Mary’s University, London, UK
Haemophilia A is one of the most common inherited bleeding disorders, caused by either deficiency or impairment in function of the factor VIII (FVIII) pro-coagulant protein. The bleeding phenotype is related to the level of residual functional FVIII. Patients with severe disease present with bleeding that is spontaneous or follows trauma or surgery and have a factor VIII activity (FVIII:C) of <1%. Treatment of bleeding episodes is through intravenous infusion of FVIII concentrate. An individual’s response to treatment will depend on the drug administered, dosage, dosage frequency and their pharmacokinetic (PK) profile.
Alteration of any of these variables may lead to great variability in an individual’s treatment response. In this article, we review how pharmacokinetics plays a crucial role in the setting of prophylactic treatment of severe haemophilia A and how pharmacokinetics is set to be of growing importance in the modern management of haemophilia. 
Pharmacokinetics mathematically describes the effects and time course of a drug in the body, looking at each part of a drug’s journey from absorption, through distribution, metabolism and elimination.(1) Pharmacokinetic studies are based on measurement of the concentration of a drug at different time points. In haemophilia A, as FVIII is exogenously produced, the activity of this protein is used as a bioassay for concentration.(2) Pharmacokinetics can be used for individualised dosing of factor concentrates, assessment of new concentrates and diagnosis of ineffective treatment (for example, development of inhibitors to FVIII). (For a detailed review of the pharmacokinetic variables see References 1 and 2).
Guidelines for pharmacokinetic studies for factor concentrates are described by the Scientific Standardising Committee of the International Society of Thrombosis and Haemostasis. For FVIII concentrates, a wash-out period of 72 hours is recommended, followed by an infusion of 25–50IU/kg. In adults, FVIII:C is measured before infusion and at ten time-points (15 minutes, 30 minutes, 1, 3, 6, 9, 24, 28, 32 and 48 hours). In patients younger than three years, a reduced schedule of five time points can be used (pre-study, 1, 10, 24 and 48 hours).(3) 
A second approach to estimation of pharmacokinetics is through population pharmacokinetic modelling. This allows concentration data from multiple pharmacokinetic studies to be fitted to a covariate and statistical model simultaneously. This is useful for combining concentration data where there are sampling differences and can be used to estimate a patient’s pharmacokinetic response based on limited sample points.(4)
Prophylaxis in haemophilia A
Although patients with severe haemophilia A have spontaneous joint bleeds and subsequent arthropathy, those with moderate haemophilia A (FVIII:C 1–5%) bleed far less frequently and have less arthropathy.(5) This observation led to the concept that prophylactic factor VIII infusions might ameliorate the phenotype of severe disease. Although used for many years based on retrospective data, recent prospective trials have demonstrated the benefit of prophylaxis in the reduction of bleeding and preservation of joint function.(6,7) Prophylaxis is the standard of care for children with severe haemophilia A to prevent arthropathy and is increasingly used in adults to reduce bleed frequency. 
Factor VIII trough levels 
A goal of prophylaxis has been to keep the FVIII:C trough level >1%. An initial retrospective study of patients on prophylaxis demonstrated a weak relationship between the time spent with a FVIII:C <1% and the incidence of joint bleeds. Of note in this study is that some patients had no joint bleeds despite FVIII:C <1% and others had joint bleeds with FVIII:C > 3%.(8)
The pharmacokinetic data of patients aged one-to-six years (children) and 10–65 years (adolescent/adults) from three clinical trials into the recombinant anti-haemophilic factor, ADVATE, has subsequently demonstrated that patients with one or more bleeds spend more time with FVIII:C <1, 2 and 5% when compared with those that had no bleeds. Time spent per week with a FVIII:C <1% was associated with an increased incidence of all bleeds and haemarthroses.
The probability of having no bleeds in a year was directly related to time spent per week with a FVIII:C <1%. For each additional hour per week that the FVIII:C was <1%, the annual bleed rate increased by 2.2% (children) and 1.4% (adolescents/adults). The time spent with a FVIII:C <1% was more important than the amount of FVIII the individual was exposed to during the week (represented by the area under the plasma concentration curve (AUC)).
As the elimination half-life (t½) decreased the number of bleeds increased in the children. No association between pharmacokinetic variables and bleeding was seen in the adolescent/adults. Compliance with FVIII infusions was one of the most important determinants of bleeding.(9)
Variables affecting response to factor VIII concentrates
Multiple variables affect an individual’s response to a drug, which are either fixed (pharmacokinetics) or modifiable (drug administered, dosage and timing between doses). Although there will also be some variation seen within an individual (intra-individual), variability to treatment is much greater between individuals (inter-individual).(10)
Pharmacokinetics in children and adults
There are clear pharmacokinetic differences between adults and children. FVIII:C is significantly lower at 48 hours post FVIII infusion in children than in adolescents/adults.(9) In adolescents/adults, the weight adjusted clearance (CL) is lower and t½ is longer.9 All pharmacokinetic parameters are generally lower in children, although a proportion of these changes may result from sampling differences. For all pharmacokinetics parameters, intra-patient variance is smaller than inter-patient variance. In children, t½ significantly increases with age, but not with ratio weight.(9)
In adolescents/adults, the Cmax and in vivo recovery (IVR) increase significantly with both age and ratio weight, although there is no relationship between t½ and age or weight. Variation in t½ leads to the greatest difference in an individual’s dosage requirements, with differences in the IVR accounting for only a modest effect. As such, an individual’s pharmacokinetics cannot be predicted from age or weight alone. 
The pharmacokinetic data from the ADVATE trials have been examined using a two-compartment population pharmacokinetic model, showing good correlation between predicted and observed FVIII:C.(4) This model has confirmed that CL is higher and t½ lower in children than in adolescents/adults, with no difference in the IVR between the two groups. This confirms that CL decreases markedly during growth and continues to decline slightly during adulthood with expected increases in the t½. As a result, the dosage that a patient requires while on prophylaxis will change throughout their life. 
Half-life and dosing schedule 
Inter-individual variability in pharmacokinetics results in a great variation in the time taken for FVIII:C to fall to <1% following an infusion of FVIII concentrate. The t½ and dose frequency have the greatest effect on FVIII:C trough levels and the time per week spent with a FVIII:C <1%. In children, t½ varies by 34.1 hours and in the adolescents/adults by 57.1 hours between those on the 5th and 95th centiles. Variation in the IVR has less effect on the time taken to reach a trough of 1% and dosage changes lead to proportional changes in trough levels. Different dosing schedules using the same total weekly dose of FVIII leads to marked differences in time spent with FVIII:C <1%. For example, alternate day dosing in a child with median t½ will result in no time with a FVIII:C <1% per week, whereas dosing every three days results in more than 24 hours a week with a FVIII:C <1%. 
Similarly, one can combine the effects of t½ and dosing frequency. Considering a fixed total dose per week, daily dosing leads to no time spent with FVIII:C <1%, even in those with the shortest t½. Dosing on alternate days or every third day leads to no time per week with a FVIII:C <1% in those with t½ above the median, but as t½ shortens the time spent per week with a FVIII:C <1% increases. As a result, patients with median or long t½ could be effectively dosed on alternate days or every three days, whereas those with a shorter t½ require more frequent infusions to maintain FVIII:C > 1%. A common approach is to give prophylaxis on a Monday/Wednesday/Friday schedule. On this schedule, patients are unlikely to maintain FVIII:C >1% for the whole weekend. 
The total amount of FVIII required per week is again dependent on the dosing schedule and t½, especially for patients with the shortest t½. A child on the 5th centile for t½ would require a weekly total dose of 153IU/kg if dosed on alternate days or 967IU/kg when dosed every three days, an almost eightfold difference. In comparison, a child on the 95th centile requires 21IU/kg or 54IU/kg using the same dosage schedules. If higher trough levels are desired, the above changes will be amplified. In patients with recurrent bleeds, a daily protocol may be more appropriate as this can significantly increase trough levels without changing the total amount of FVIII used.(11) 
Inter-product variability in pharmacokinetics
There may also be differences in the pharmacokinetic profile of different coagulation factor concentrates. For FVIII concentrates there are subtle differences in the pharmacokinetics of the different concentrates used. Full-length recombinant products have a lower CL and volume of distribution at steady state, with marginal differences in IVR and t½ than plasma-derived products.12 In haemophilia B (factor IX deficiency), however, the pharmacokinetic profile of recombinant products is significantly different to that of plasma derived products which significantly impacts on dosing.(12,13)
Personalised medicine and future treatments
Until recently, pharmacokinetics has primarily been used as a research tool and to characterise new coagulation factor concentrates. With increased appreciation of how pharmacokinetics impacts on an individual’s treatment, a change in current dosing practice is required. Usage of pharmacokinetics has the potential for cost-effective usage of concentrates as well as a reduction in bleed frequency through personalised dosing. Although trough levels of 1% are used to guide prophylaxis, this level will not be appropriate to all patients.(8) An individual’s requirements will also be related to level of activity and their bleeding phenotype. Trough levels might be more important in patients with a relatively sedentary lifestyle whereas peak (Cmax) levels may be of more importance in patients involved in sporting activities. 
Clinical trials are ongoing into modified FVIII products aiming to improve their pharmacokinetic and immunological profiles. These modifications include chemical modification (for example, PEGylation, glyco-PEGylation and polysialylation), fusion to protein conjugates (for example, Fc-IgG fusion and albumin fusion) and site-directed mutagenesis.(14) This could lead to less frequent injections for patients. In lengthening the t½ of a product, assuming the dose kinetic curves are similar to existing products, the variability in t½ will be amplified. For example, if a concentrate has a t½ of 36 hours (range 24–48 hours), an infusion of 30IU/kg would lead to a variation of 6–11.8 days in the time taken for the FVIII:C to fall to 1%.(13) This will mean that knowledge of an individual’s pharmacokinetics will become even more important when prescribing these newer concentrates.
Prophylaxis is a well-established part of the management of haemophilia A in developed countries. An individual’s pharmacokinetic profile and dosing schedule has a significant impact on the likelihood of a successful prophylactic strategy. Based on this, as well as on variation in bleeding phenotypes, there is clearly not a standard prophylactic protocol that will suit all patients. Treatment based on weight alone will lead to significant over-treatment in some and under-treatment in others, with the increased risk of breakthrough bleeds. Appreciation of an individual’s pharmacokinetic profile is critical for the individualisation of a prophylactic regimen and for cost-effective use of factor concentrates. If there is a move towards a lower dose being given regularly (daily), there will be a need for smaller vial sizes of FVIII concentrates to allow for more flexible dosing.(13) The application of population pharmacokinetics through existing software has the potential to simplify calculating an individual’s pharmacokinetic parameters to individualise treatment at the bedside.
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  2. Shapiro AD, Korth-Bradley J, Poon MC. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia. Haemophilia 2005;11(6):571–82.
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  5. Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand Suppl 1965;Suppl 77:3–132.
  6. Manco-Johnson MJ et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535–44.
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  10. Bjorkman S et al. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010;8(4):730–6.
  11. Collins PW et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2010;8(2):269–75.
  12. Berntorp E, Bjorkman S. The pharmacokinetics of clotting factor therapy. Haemophilia 2003;9(4):353–9.
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  14. Fogarty PF. Biological rationale for new drugs in the bleeding disorders pipeline. Hematol Am Soc Hematol Educ Program 2011;2011:397–404.