Implementation of pharmacokinetic-guided dosing of prophylaxis in hemophilia patients

Rationale:

Most severe and some moderate severe hemophilia patients receive prophylactic treatment with factor concentrate to prevent spontaneous bleeding in joints and muscles, decreasing the risk of arthropathy and long term disability. Currently, initial dosing of prophylaxis is based on body weight and, often hypothetically on maintenance of minimal factor VIII (FVIII) or factor IX (FIX) concentrate trough levels of 0.01 international units per milliliter (IU/mL) in both hemophilia A and hemophilia B. However, these trough levels are rarely measured, and dosing regimens are generally adjusted only when clinically relevant bleeding occurs, not taking microbleeds into account. Furthermore, it is well known that a large interindividual variability exists in the pharmacokinetics (PKs) of factor concentrates in patients. Therefore, PK-guided dosing may lead to more optimal safeguarding of FVIII and FIX trough levels and awareness of actual FVIII and FIX peak levels. Moreover, PK-guided dosing may help to achieve higher trough and peak levels when clinically indicated due to activity pattern and provide support with regard to the introduction and dosing of novel extended half-life (EHL) concentrates. Importantly, always taking cost and benefit of treatment into account in all settings. In this study, we hypothesize that FVIII/FIX trough and peak levels as set by treating physician can be predicted and achieved more effectively by application of PK-guided prophylaxis.

To analyze this, hemophilia patients treated prophylactically will be enrolled in the study and categorized according to type of hemophilia (hemophilia A or hemophilia B) and type of concentrate (standard half-life (SHL) or EHL). Severe hemophilia patients (FVIII/ FIX<0.01 IU/mL) on prophylaxis will be analyzed separately from non-severe hemophilia patients on prophylaxis (FVIII/ FIX¡Ý0.01 IU/mL).

Objective:

To investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B patients.

Study design:

Multicenter, non-randomized, prospective cohort study.

In addition, in those cases where systematically collected retrospective data of individual patients is available of administered factor concentrates and achieved FVIII/FIX levels, this will be utilized to enrich individual PK profiles and to fortify available population PK models (“real life data”).

Study population:

Hemophilia A and B patients of all ages on prophylaxis.

Chronological interventions:

After study inclusion, patient characteristics and demographics will be collected by study team. All patients will fill in the Visual Analogue Scale (VAS: start of study), Hemophilia Activities List (HAL) and/or pediatric HAL (PedHAL). The Hemophilia Joint Health Score (HJHS, or performed <12 months prior) will be performed or must have been performed <12 months prior. All patients will undergo the following interventions:

PK-profiling

All individuals will undergo individual PK-profiling according to study protocol (Appendix Table 1), with infusion of specified dose of factor concentrate and set blood sampling time points depending on type of hemophilia and type of factor concentrate. Three prior infusions and time points of infusion should be documented.
No wash out period for factor concentrate is necessary during PK-profiling, due to application of population PK modeling and the ability to simulate baseline data when prior doses of factor concentrate are known.

Initial PK-guided treatment (12 weeks)

Dosing will be advised by clinical pharmacologist on the basis of FVIII/ FIX target trough and peak values set by treating physician, in accordance to patient characteristics, activity pattern and in consultation with patient/ caretakers. Patients will be initially on PK-guided treatment for 12 weeks. At set time points, according to protocol, plasma concentrations will be tested and compared to predicted FVIII/ FIX values to validate predicted dosing regimen.
In all collected data, meticulous documentation of exact doses, timing of dosing and timing blood sampling is obligatory.



Follow-up treatment under PK-guidance (24 weeks)

A follow up period of 24 weeks is prescribed to clinically follow patients on PK-guided treatment in order to collect more extensive data to establish the association between target levels and bleeding events. At the end of the follow-up period, blood sampling will be performed and all patients will again fill in the VAS (end of study), HAL or PedHAL and the next annual HJHS will be performed.

Main study parameters/endpoints:

Primary endpoint

1. Observed trough and peak FVIII and FIX levels in comparison to predicted FVIII and FIX levels by population PK-modeling (predictive performance).

Secondary endpoints

1. Association of (real life or simulated) FVIII/FIX (trough and peak levels) with bleeding episodes and daily activities.
2. Expectations, feasibility and experience with PK-guided dosing with the different factor concentrates (standard half-life versus extended half-life) as reported by patient/ caretakers and physician will be measured using a Visual Analogue Scale (VAS) at the start and end of the study (Appendix VAS).

3. Economic analysis in which costs and benefits of standard prophylactic treatment and PK-guided prophylaxis are compared.

4. Analysis of modifiers effecting PK parameters of FVIII/FIX concentrate in order to further optimize population PK models.

We hypothesize that FVIII/FIX trough and peak levels as set by treating physician can be predicted and achieved more effectively by application of PK-guided prophylaxis.

Primary outcome: At time points (at least the blood sampling moments during the initial PK-guided period of 12 weeks and during the follow-up period of 24 weeks). FIX levels one year before inclusion will be simulated backwards based on PK-profiling.

Secondary outcomes:

1. whole study period (prospective and retrospective period)

2. whole study period (measured using a VAS at start and end of the study)

3. whole study period (prospective and retrospective period)

4. whole study period (prospective and retrospective period)

Stratum 1(A/B): Hemophilia patients on SHL prophylaxis undergo individual PK-profiling on SHL. During an initial total period of 12 weeks, all patients will be on PK-guided treatment dosing. Periodic blood sampling during PK-guided treatment should be divided between subsequent FVIII/FIX dosages and should represent minimal a trough, peak and a FVIII/FIX level between trough and peak. Thus, a minimum of three blood sampling moments will be planned divided over twelve weeks.The first 10 weeks of this period will be blinded. Then, during the last 24 weeks, patients will be followed on PK-guided treatment. At the end of this follow-up period, blood sampling will be performed.

Stratum 2(A/B): Hemophilia patients switching to or on EHL prophylaxis undergo individual PK-profiling on SHL. Patients will be asked to undergo individual PK-profiling on SHL concentrate as well. During an initial total period of 12 weeks, all patients will be on PK-guided treatment dosing. Periodic blood sampling during PK-guided treatment should be divided between subsequent FVIII/FIX dosages and should represent minimal a trough, peak and a FVIII/FIX level between trough and peak. Thus, a minimum of three blood sampling moments will be planned divided over twelve weeks. Then, during the last 24 weeks, patients will be followed on PK-guided treatment. At the end of this follow-up period, blood sampling will be performed.