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Department of Hematology
Wayne State University
Division of Hematology/Oncology
Children's Hospital of Michigan
Michael Callaghan, MD, has disclosed that he has received consulting fees from Bayer, BioMarin, Catalyst, Hema Biologics, Roche/Genentech, Sanofi, Spark, and Takeda.
With the advent of extended half-life products and better tools for assessing pharmacokinetics (PK), our goals for managing hemophilia have evolved beyond simply preventing bleeding and joint damage. We now aim to enable people with hemophilia to engage in life as they would if they did not have hemophilia. Below, I share how I personalize treatment so that my patients with hemophilia can participate more fully in life.
Challenge: Variability in Clearance of Factor VIII
A key challenge in the care of patients with hemophilia is the marked variability in how they respond to factor VIII, as shown in their different peak levels and clearance rates after a given dose. A patient who clears factor VIII more quickly will spend more time with their factor VIII levels below 1%, which imparts a higher risk of bleeding. One approach to overcoming this challenge is to administer higher or more frequent doses of factor VIII, but that can be difficult for families, and for patients to have to obtain IV access and spend time infusing. Another approach is to use extended half‑life products that allow for less-frequent dosing and/or higher trough levels.
PK-Guided Prophylaxis: Supporting Data
The utility of extended half-life products allowing for higher trough levels to prevent bleeding was examined in a recent phase IIIb/IV trial, PROPEL. Patients with severe hemophilia A were randomized to receive PK-guided prophylaxis with recombinant pegylated FVIII targeted to a low trough of 1% to 3% vs a higher trough of 8% to 12%, which was achieved with higher doses and more frequent dosing.
At the International Society on Thrombosis and Haemostasis (ISTH) congress in 2019, Klamroth and colleagues reported that a numerically greater percentage of patients in the high-trough group had 0 bleeds: 62%, vs 42% in the low-trough group (P = .0545). The high-trough group had a lower mean total annualized bleeding rate compared with the low-trough group (1.6 vs 3.6, respectively). The high-trough group also demonstrated a lower mean spontaneous bleeding rate (0.5 vs 2), consistent with our expectations that spontaneous bleeds would occur more frequently in patients with severe hemophilia and factor levels below 1%.
Individual PK Profiling
The data from PROPEL show that if we know a patient’s intrinsic PK, we can adjust their dosing schedule and/or aim for higher troughs to potentially prevent more bleeding. However, we are faced with the conundrum of how to obtain the PK data for each patient—an onerous procedure that typically requires sampling blood at 7-10 timepoints throughout the 48 hours after infusion.
To avoid this burdensome procedure, the ISTH recommends performing limited sampling and then using modeling to estimate a patient’s PK profile. Björkman and colleagues determined when the limited samples should be obtained using population PK modeling. Although both the early and very late timepoint samples were not very informative, the limited samples were as informative as conventional approaches if collected at 4-8, 16-28, and 40-60 hours after infusion. These limited samples could then be used with Bayesian statistics to estimate the patient’s PK profile.
There are 2 well-known online or app‑based Bayesian tools available for helping clinicians implement this limited-sample approach. The interfaces are straightforward: You can input the desired dose and receive an estimated dosing interval based on your patient’s data, or vice-versa; you can also input the desired peak and trough and get a recommend regimen.
The first tool is an extended half-life factor VIII manufacturer’s tool called myPKFiT®, which is approved by the FDA for use in adults and children with hemophilia A who are receiving the manufacturer’s prophylaxis product, a recombinant antihemophilic factor. The second tool comes from WAPPS‑Hemo, a global network of hemophilia treatment centers that has developed an extensive repository of factor concentrate PK data across a wide variety of products. They offer myWAPPS, a personalized PK monitoring app, for patients. Because the WAPPS‑Hemo database is so extensive, their tool allows for quite limited sampling (ie, 2-3 blood draws) that can then be used to design a regimen.
I use these tools both for optimizing treatment and for educating my patients. I like to sit down with the patient and ask them, “What’s going on for the week?” We can then try to align when the patients will be undergoing peak activities and/or at the highest risk of bleeding with the time that their factor levels will be the highest. Furthermore, the patient can also use the patient version of the applications to estimate what their factor level will be in the future based on their dose and other parameters—thereby enabling them to plan for an activity, like a hike in 2 days.
I think when patients understand that this is possible, they feel empowered. This shared decision-making also increases adherence. Finally, using these tools to better tailor treatment has the benefit of decreasing treatment burden by spacing out doses, or even decreasing cost by using more appropriate doses in a patient with an intrinsically long half‑life product.
How do you use PK data to personalize hemophilia prophylaxis for your patients? Do you use conventional sampling or limited sampling? Please share your perspective in the comments box.