Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice

Abstract

The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient's individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using non-linear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, twenty models for FVIII and seven for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only four reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Shifting Paradigms and Arising Concerns in Severe Hemophilia A Treatment

“…Hence, using an incorrect tool for a particular PK evaluation may lead to unreliable outcomes. [141][142][143] Applications for patient diaries like haemtrack, HaemoAssist 2, smart medication, florio HAEMO, and myPKFiT have been devised to enable patients to record bleeding events and administered doses. These applications can also notify patients when they reach critical factor levels to prevent missed FVIII infusions.…”

“…Depending on PK for bleeding control may be unreliable if the standard of home monitoring is unsatisfactory. 143 PK analysis could be used to recognize patients with extended FVIII half-lives, enabling them to lessen their dosage and/or dosing frequency. This will eventually reduce treatment costs and be more convenient for children, older people, and others with poor venous access.…”

“…Thus, randomized controlled trials with extended follow-up periods are required to compare standard dosing with PK-guided prophylaxis incorporating personalized target levels exceeding 1 IU/dL. 143 Moreover, the need for expertise in analyzing and understanding PK results poses a significant challenge for the implementation. According to International Society on Thrombosis and Haemostasis survey, only 9.7% of doctors conducted PK analysis when changing from SHL to EHL factor concentrates primarily because of restricted time, accessibility, and resources.…”

“…Despite the development of PK/PD models, they have yet to be validated or practiced with patients. 143,151…”

The Impact of Pharmacokinetic-Guided Prophylaxis on Clinical Outcomes and Healthcare Resource Utilization in Hemophilia A Patients: Real-World Evidence from the CHESS II Study

“…17,18 However, data from controlled clinical trials are limited, and information on the benefit of targeting higher FVIII trough levels has therefore been derived from a modeling approach. [19][20][21][22][23] The recent phase 3, prospective, randomized, open-label, multicenter PROPEL study (NCT02585960) evaluated the safety and efficacy of the EHL recombinant FVIII rurioctocog alfa pegol at two PK-guided target FVIII trough level ranges (1-3% and 8-12%). This study demonstrated that a higher proportion of patients achieved zero bleeds when an elevated FVIII trough level was targeted.…”