Pharmacokinetics and the transition to extended half‐life factor concentrates: communication from the SSC of the ISTH

Abstract

Extended half-life proteins (EHL) are increasingly used in clinical practice, but there is no standardized approach to sampling, interpretation and implementation of pharmacokinetics (PK) data to maximize treatment benefit. The goal of EHL treatment is to attain a trough level sufficient to protect against spontaneous bleeds and reduce infusion frequency and limitations on individual activity and lifestyle. Performing classical PK assessments requires multiple blood samples, which is burdensome for patients and providers. Herein we review a population pharmacokinetic (popPK) approach to estimate individual PK parameters to transition patients from standard half-life (SHL) to EHL concentrates. We propose that a minimum of two to four post-infusion samples is sufficient to estimate individual PK profiles, with sufficient certainty to maintain factor levels above 1% and achieve bleed-free lifestyles. We also survey current PK use in patients transitioning to EHL, review key PK parameters and popPK models, and recommend an approach to using PK in patients initiating or switching to EHL.

Regional variation and cost implications of prescribed extended half‐life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia

“…Although there have been no head‐to‐head comparisons, clinical trial data do not suggest a difference between the ability of SHL and EHL concentrates to achieve hemostasis in the setting of an acute bleed. Despite significant interpatient variation in the half‐life of both SHL and EHL CFCs, routine implementation of pharmacokinetic (PK) profiles to inform prophylactic dosing regimens has not occurred in the United States . There is increasing evidence of the positive impact of PK‐tailored prophylaxis on bleed rates, longitudinal joint health, resource utilization and patient‐reported outcomes …”

“…Despite significant interpatient variation in the halflife of both SHL and EHL CFCs, routine implementation of pharmacokinetic (PK) profiles to inform prophylactic dosing regimens has not occurred in the United States. 15,16 There is increasing evidence of the positive impact of PK-tailored prophylaxis on bleed rates, longitudinal joint health, resource utilization and patient-reported outcomes. [17][18][19][20] The primary objective of this study was to investigate longitudinal change in use of SHL and EHL CFCs among patients with moderate and severe haemophilia A or B using the ATHNdataset.…”

Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review

“…Common practice in this scenario is that either the dose is initially kept the same as before the switch and frequency is adjusted proportionally to the relative expected change in terminal half‐life, or the dose and frequency tested in the pivotal studies are used in a first instance. Current guidelines suggest initiating extended half‐life (EHL) products at the same dose as standard half‐life concentrates but reducing the infusion frequency from 3 to 2 times weekly, and subsequently adjusting the dose based on a population pharmacokinetic (PopPK) approach . When a person with hemophilia switches between factor concentrates, the person is switching from a product with known PK, or at least with known outcomes (eg, dose required to reduce bleeding events), to one with unknown PK.…”

Clinical application of Web Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS‐Hemo): Patterns of blood sampling and patient characteristics among clinician users

“…Use of PopPK eliminates the need for a washout period and dense blood sampling following CFC infusion when performing PK analysis. 11,15,24 Success of PK-guided prophylaxis with respect to the potential for increased trough factor levels and reduction in factor concentrate utilization has been modelled and also demonstrated in small cohorts of primarily haemophilia A patients. Increasingly, PopPK models and interfaces have become available to clinicians.…”

“…The FVIII and FIX subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) recently published guidance on the use of PopPK in haemophilia management, suggesting postinfusion blood sampling windows for both standard half-life (SHL) and extended half-life (EHL) FVIII and FIX CFCs. 11,15,24 Success of PK-guided prophylaxis with respect to the potential for increased trough factor levels and reduction in factor concentrate utilization has been modelled and also demonstrated in small cohorts of primarily haemophilia A patients. 6,9,10,12 While the implementation of PK-tailored prophylaxis is increasingly featured at national and international congresses in both educational sessions and the scientific programmes, utilization of PopPK profiles in clinical practice remains vague.…”