Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations

Abstract

ObjectivesIn a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia.MethodsThe members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript’s scope and structure, taking into account comments from the external feedback to the earlier document.ResultsMany clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half‐life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head‐to‐head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future.ConclusionsTraditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol.

Multicentre pharmacokinetic evaluation of rFVIII‐Fc (efmoroctocog alfa) in a real life and comparison with non‐extended half‐life FVIII concentrates

“…This limitation prompted us to analyse FVIII levels measured in 47 haemophiliacs using the WAPPS-Hemo population PK model, which is more accurate and reliable in case of limited sampling protocol. 18 With this population PK method analysis, the FVIII half-lives measured were similar to those previously evaluated, and our data confirmed the longer half-life of efmoroctocog alfa (12.9 hours) compared to those of non-EHL FVIII was similar to that reported by Mahlangu,5 and highly variable from one patient to another in accordance with another study, with ratio values ranging from 0.79 to 2.98 in treated children. 6 Actually, the relative benefit of switching from a non-EHL FVIII to efmoroctocog alfa appeared to be the same whatever the age and mainly influenced by basal VWFAg levels.…”

Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX‐Fc fusion protein: A randomized trial

“…However, published PK data for N9-GP and rFIXFc are not directly comparable due to key differences in trial designs and PK analysis methodologies. 19 Therefore, the aim of this trial was to perform a direct, single-dose PK comparison between N9-GP and rFIXFc.…”

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

“…The addition of PK-tailored dosing may facilitate a provider's ability to individualize haemophilia prophylaxis, [5][6][7][8][9] maximizing the musculoskeletal health of patients by increasing trough levels while minimizing factor concentrate consumption. [15][16][17] Within the haemophilia A population an association has been demonstrated between an increased risk of musculoskeletal bleed events and duration of time (hours per week) an individual spends with FVIII activity levels below 1 IU/dL. [15][16][17] Within the haemophilia A population an association has been demonstrated between an increased risk of musculoskeletal bleed events and duration of time (hours per week) an individual spends with FVIII activity levels below 1 IU/dL.…”

“…[15][16][17] Within the haemophilia A population an association has been demonstrated between an increased risk of musculoskeletal bleed events and duration of time (hours per week) an individual spends with FVIII activity levels below 1 IU/dL. 15,19,20 Historically, incorporation of PK into routine clinical practice has been impeded by the rigorous sampling required for classical PK methodology, 21,22 limited access to provider-friendly tools for PK analysis, and provider and patient uncertainty about the magnitude of improvement to be gained by adding PK information to decision-making. Use of PopPK eliminates the need for a washout period and dense blood sampling following CFC infusion when performing PK analysis.…”

“…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.…”