Sven Björkman

Consensus perspectives on prophylactic therapy for haemophilia: summary statement

Summary.  Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long‐term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality‐of‐life assessment instruments, and cost‐benefit analyses.

Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

Summary.  Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL−1. Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate. Objectives: To assess the effect of FVIII level on break‐through bleeding in patients with severe hemophilia A on prophylaxis. Patients/methods: This study analysed data from 44 patients aged 1–6 and 99 patients aged 10–65 years with severe hemophilia A (FVIII <1 IU dL−1) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate®). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL−1. Results: The data demonstrate that increasing time with a FVIII below 1 IU dL−1 is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1–6 years, the rate of bleeding was also influenced by FVIII half‐life and clearance. Conclusions: These data have important implications for the management of patients with severe hemophilia.

Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia

Haemophilia is a recessively inherited coagulation disorder, in which an X-chromosome mutation causes a deficiency of either coagulation factor VIII (FVIII) in haemophilia A, or factor IX (FIX) in haemophilia B. Intravenous administration of FVIII or FIX can be used to control a bleeding episode, to provide haemostasis during surgery or for long term prophylaxis of bleeding. In special cases, activated factor VII (FVIIa) may be used instead of FVIII or FIX. The aim of this work is to review the pharmacokinetics of FVIII, FIX and FVIIa and to give an outline of the use of pharmacokinetics to optimise the treatment of patients with haemophilia.The pharmacokinetics of FVIII are well characterised. The systemic clearance (CL) of FVIII is largely determined by the plasma level of von Willebrand factor (vWF), which protects FVIII from degradation. Typical average CL in patients with normal vWF levels is 3 ml/h/kg, with an apparent volume of distribution at steady state (Vss) that slightly exceeds the plasma volume of the patient, and the average elimination half-life (t 1/2) is around 14 hours. There are still some discrepancies in the literature on the pharmacokinetics of FIX. The average CL of plasma-derived FIX seems to be 4 ml/h/kg, the Vss is 3 to 4 times the plasma volume and the elimination t 1/2 often exceeds 30 hours. FVIIa has a much higher CL (average of 33 ml/h/kg), and a short terminal t 1/2 (at 2 to 3 hours). The Vss is 2 to 3 times the plasma volume.Since the therapeutic levels of coagulation factors are well defined in most clinical situations, applied pharmacokinetics is an excellent tool to optimise therapy. Individual tailoring of administration in prophylaxis has been shown to considerably increase the cost effectiveness of the treatment. Dosage regimens for the treatment of bleeding episodes or for haemostasis during surgery are also designed using pharmacokinetic data, and the advantages of using a constant infusion instead of repeated bolus doses have been explored. The influence of antibodies (inhibitors) on the pharmacokinetics of FVIII and FIX is in part understood, and the doses of coagulation factor needed to treat a patient can tentatively be calculated from the antibody titre.In conclusion, therapeutic monitoring of coagulation factor levels and the use of clinical pharmacokinetics to aid therapy are well established in the treatment of patients with haemophilia.

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

Summary.  The pharmacokinetic (PK) response to factor VIII (FVIII) and factor IX varies between patients and this has important clinical implications for treatment. Although PK is affected by patient characteristics, this relationship is too weak to infer a result for an individual and, if required, PK must be measured. An important determinant of the efficacy of prophylaxis is the length of time an individual spends with a low level of coagulation factor. This time is more dependent on the patient’s coagulation factor half‐life and the frequency of dosing than in vivo recovery and dose infused. Improved understanding of the effect of PK and dose frequency on factor levels in patients on prophylaxis will help tailor regimens to individuals better and allow more cost effective use of coagulation factor concentrates. Calculations suggest that adults need less FVIII per kg body weight than children. The effect of half‐life on trough levels questions the logic of Monday, Wednesday, Friday dosing and suggests a role for innovative regimens including low‐dose daily treatment which leads to either higher trough levels or decreased FVIII requirement. This may expand access to prophylaxis in healthcare systems with limited resources and potentially improve patient outcomes. The ideal trough level will vary between individuals and at different times of their lives and may be <1 IU dL−1. If PK is to be used in routine clinical practice, a simplified method for its measurement is required and this methodology is becoming available.

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

Summary.  Background: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. Objectives: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter‐patient variability in pharmacokinetics and different dosing regimens on trough levels. Methods: Simulations used FVIII half‐lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin‐Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. Results and conclusions: Half‐life and dose frequency had a larger effect on trough FVIII and time per week with FVIII < 1 IU dL−1 than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter‐patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg−1 and some would require more than 400 IU kg−1. Knowledge of individual patients’ half‐lives and alteration of frequency of infusions may allow the more cost‐effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.

A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia

Summary.  The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmö haemophilia treatment centre during a 6‐year period. A retrospective survey of medical records for the years 1997–2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and ‘other bleeds’) was compiled. The patients were stratified by age (0–6, 7–12, 13–18, 19–36 and >36 years) and joint score (0, 1–6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty‐one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient‐years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high‐dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re‐assessment and individual dose tailoring.

Population pharmacokinetics of recombinant factor VIII : the relationships of pharmacokinetics to age and body weight

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.

Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis

The aims of this study were to investigate possible age‐related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4–56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer‐simulated from the single‐dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half‐life of FIX:C showed no correlation with age, while in vivo recovery (in U dL–1 per U kg–1 given) tended to increase. Computer‐predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg–1) and, conversely, doses (in U kg–1) needed to maintain a 1‐U dL–1 trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1‐U dL–1 trough level can normally be maintained by dosing every 2–3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.

Pharmacokinetic dosing in prophylactic treatment of hemophilia A

Abstract: The aim of this study was to investigate individual pharmacokinetics as a tool for dosing of factor VIII (FVIII) in severe hemophilia A. It is assumed that effective prophylaxis against bleedings is maintained if the plasma FVIII:C activity is kept above 1 U/dl, and the present study is based on this assumption. A current standard dosage regimen for FVIII is 25–40 U/kg up to three times weekly. However, there is considerable individual variation in the pharmacokinetics of FVIII:C. Individual pharmacokinetic data were used to computer‐simulate plasma activity curves after repeated doses in 8 patients. Going from prophylaxis regimens of normally 2–3 infusions per week to dosing every 2 days would theoretically reduce their average FVIII consumption by 43% with maintained or increased trough levels of FVIII:C. Daily dosing would reduce their mean FVIII usage by 82%. Modified dosage regimens, infusions every 2 days, were implemented in the patients, and plasma samples were drawn to verify the pharmacokinetic models. The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed. Dosing of coagulation factors according to kinetic principles can result in more cost‐effective utilization of these very expensive preparations.

Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A

The aim of the study was to investigate the feasibility of optimizing prophylactic dosing of factor VIII by the use of individual pharmacokinetic data. Twenty‐one patients were enrolled in a randomized cross‐over study on standard dosage regimens vs. dosing according to pharmacokinetic principles. The study period was 2×6 months. Using single‐dose pharmacokinetic data for each patient, plasma factor VIII procoagulant activity (FVIII:C) curves following various doses and intervals were computer‐simulated. From these calculations, a suitable dosage was chosen. FVIII:C was also repeatedly measured during study periods. Trough levels of FVIII:C, numbers of spontaneous joint bleedings and amounts of factor concentrate used during the two study periods were compared for each patient.