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Personalised treatment


clotting factor activity, PK of


FVIII: C (U/dL)


100 10 1


0.1


100 10 1


0.1


100 10 1


0.1 0


770 IU/week 3


6 9 Time (days) Figure 1: Tailoring with short-acting concentrate prophylaxis regimens19


FVIII needed to achieve a desired trough level, dose frequency and half-life of FVIII concentrates have a more significant influence than the dose per kg and the in vivo recovery.


Individual- versus population- based pharmacokinetics


One of the key elements needed to target a specific trough level and tailor prophylaxis is the estimation of the pharmacokinetics (PK) disposition of factor VIII at an individual level. The main barriers to PK assessments in clinical practice are, however, the burden of the extensive multiple blood sampling required over 24–72 hours (usually 11 points for the classical approach) and the inconvenience for the clinician to perform the needed calculation, which are often beyond the expertise of most haemophilia treaters. These practical difficulties have limited the use of PK information in clinical practice. Population pharmacokinetics, which appears as a promising alternative is a relatively young science that couples notions and methods from clinical epidemiology, Bayesian probability and classical pharmacokinetics, allowing easier but reliable estimation of individual parameters using a few points from each individual and all previous knowledge from the entire population. After years of widespread use in oncology and transplantation, it has been recently shown that population pharmacokinetics can be applied to conveniently assess, with a reduced number of plasma samples, the pharmacokinetics of FVIII. The Bayesian estimation method26


uses a population PK


model based on FVIII levels from a large population of patients as a mathematical/


statistical framework to estimate the PK in an individual patient from minimal data. The technique has been explored for FVIII27 in a limited number of patients. Using this strategy, a patient’s coagulation factor half-life may be calculated from two or three time points. In practice, a patient could take a morning dose of FVIII prophylaxis (no wash out is indeed required), and come to the clinic for a blood sample at a convenient time after school or work on two consecutive days. This methodology can facilitate measurement of PK in routine clinical practice and should be more widely implemented in clinical practice.


12


110 IU, daily 15


18 1575 IU/week 450 IU, every two days 6000 IU/week 2000 IU, three times a week


administered clotting factor concentrates, and presence of prothrombotic markers, there is evidence to suggest that variations in other coagulation proteins, as assessed in tests of global haemostasis, as well as the fibrinolytic system, can affect the clinical severity of bleeding. A possible explanation is that FVIII replacement affects patients’ global blood clotting systems differently,29


and studies


that investigate whether tailoring prophylaxis based on thrombin generation or thromboelastography rather than factor level will be of interest. Mediators of the inflammatory response in the synovium are also likely to impact the severity of joint damage in these patients. A detailed understanding of all factors that may contribute to joint damage in severe haemophilia should help us in tailoring therapy for these individuals.


Adjustment of prophylaxis Prophylaxis should be tailored to minimise joint and significant soft tissue bleeds. This adjustment is best done collaboratively between the person with haemophilia or their family and their haemophilia centre, and relies heavily on an accurate record of bleeds and treatment. Prophylaxis should be adjusted based on the observed pattern of bleeds, times of expected physical activity and the status of the individual’s


“A detailed understanding of all factors that may contribute to joint damage in severe haemophilia should help us in tailoring therapy”


The phenotypic heterogeneity of severe haemophilia Not only do patients with severe haemophilia show wide variability in their response to treatment, they also exhibit marked phenotypic variability. It has been long recognised that 10–15% of patients with ‘phenotypically characterised’ severe haemophilia have relatively mild disease clinically. Not all these patients have frequent spontaneous bleeding and, even among those who bleed, the extent of joint damage tends to vary considerably. The basis for this difference has not been completely understood. The possible determinants of this phenotypic variation in patients with severe haemophilia have been recently reviewed.28


Apart from the well-recognised associations of the level of residual


musculoskeletal system. For example, if a person on prophylaxis has had no breakthrough bleeds and their trough level is measured at 6%, then their dose of FVIII could be halved and their trough would still be 3%. If an individual has a target joint, then a period of more intensive prophylaxis that sustains a higher trough can be tried. Once the joint has settled, the regimen can be reduced. If bleeds occur in relation to a specific activity, the timing of the infusions can be adjusted to provide better cover. The regimen may be better adjusted if pharmacokinetic data are available that give information about the factor level at the time of the break-through bleeds or anticipated activity. It is common practice to infuse prophylaxis on a Monday, Wednesday and Friday. This has the


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