Improved Clinical Outcomes and Replacement FVIII Consumption in Patients with Hemophilia a after Prophylaxis Adjustment Using a FVIII Pharmacokinetics Estimation Based on Bayesian Models
Authors: Mingot-Castellano Maria Eva , Parra Rafael , Nuñez Ramiro , Martorell Marta , Heiniger Mazo Ana Isabel 
Published: October 2019

Abstract
INTRODUCTION
Current guidelines recommend that subjects with severe hemophilia A (HA) receive prophylaxis in order to prevent severe bleeding and recurrent hemarthrosis that lead to the development of arthropathy, an extremely painful and disabling condition. Success of this approach greatly depends on treatment individualization, and the pharmacokinetics (PK) of factor VIII (FVIII) replacement therapy in a given patient is a crucial consideration.
Standard PK studies require extraction of 6 to 10 samples, a procedure that takes several hours and causes adult patients and the parents of pediatric patients to miss work and children to miss school. This represents a significant barrier for routine performance of PK tests, and more rapid methods are needed in order to universalize PK-based adjustment in clinical practice.
Björkman et al. developed a method to estimate PK parameters of factor FVIII using Bayesian models (Haemophilia 2010, 16(4):597-605). This approach requires only 2-3 blood extractions between 4 and 48 h after infusion, and may help introduce PK-based tailoring in hemophilia clinics. Based on this methodology, an online tool was developed to perform PK estimates in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15).
This report describes the impact of using this tool to adjust prophylaxis regimens in clinical practice, in terms of clinical bleeding and joint bleeding rates and FVIII consumption, in subjects with HA receiving prophylaxis.
METHODS
This is an observational case series of 3 Spanish centers. Thirty-four patients were evaluated (30 severe and 4 moderate HA) aged 7-52 years (median 22 years). All were receiving prophylaxis, and all received Advate® as replacement factor.
myPKFiT® was used for estimations in 2014-2015. FVIII trough levels were adjusted between 1% and 2%. We evaluated the annual bleeding rate (ABR), the annual joint bleeding rate (AJBR) and annual FVIII use before and after PK adjustment of prophylaxis using the study tool.
RESULTS
Of the 34 patients,16 had not previously undergone a PK study (NPAP group), while 18 had already had their therapy previously adjusted by trough FVIII levels determination (PAP group). Most patients (n = 23) were following an M/W/F infusion schedule before myPKFiT® study. Median weight was 60 kg (interquartile range [IQR] = 32-78). Two samples were used for determinations in 27 patients, 3 in 5, and 4 in 2. Median FVIII half-life calculated with the study tool was 11.95 h (IQR = 10.13-14.33); median clearance was 0.035 dl/h/kg (IQR = 0.027-0.042), and median time until FVIII level 1% was 59.5 (IQR = 50.8-72.0).
FVIII use, ABR and ABJR before and after adjustment with the parameters provided by myPKFiT® are summarized in Table 1. Adjustment had an impact in the individual factor consumption of most patients: in 14 cases, the annual amount was reduced (mean −34824 ± 49925 IU/year), and in 16 it was increased (mean +60605 ± 43517 IU/year). However, this did not have a significant impact in the mean amount used in the whole series compared to that used the year prior to myPKFiT-adjusted prophylaxis (p = 0.196). Regarding clinical outcome, ABR and AJBR were both significantly reduced in the NPAP group, where 68.7% and 62.5% of patients reduced their ABR (p = 0.008) and AJBR (p = 0.008), respectively, after adjustment. These rates were generally maintained after myPKFiT-based personalization in the PAP group.
CONCLUSIONS
Clinical experience in this series suggests that PK-adjusted prophylaxis by means of a tool such as myPKFiT® may have a favorable impact on the prophylaxis regimens of HA patients. Clinical benefit can be achieved in patients whose therapy has not previously been adjusted using PK-based methods, and this personalized approach can reduce bleeding rates without significantly increasing the overall cost of FVIII therapy. Furthermore, the maintenance of bleeding rates in patients with prophylaxis previously adjusted by determination of trough levels suggests that outcomes with this method might be comparable.

Disclosures
Mingot-Castellano: Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Parra:Baxalta: Consultancy.