Application of Pharmacokinetics Programs in Optimization of Haemostatic Treatment in Severe Hemophilia a Patients: Changes in Consumption, Clinical Outcomes and Quality of Life
Authors: Mingot-Castellano María Eva , Díaz-Canales Dana , Tamayo-Bermejo Rocio , Heiniger-Mazo Ana Isabel 
Published: October 2019

Abstract
BACKGROUND: Replacement therapy with factor VIII (FVIII) in patients with severe hemophilia A has a high cost. To optimize this consumption without an increase in bleeding events or a delay in the recovery of these bleeds is a question of great interest for any Health System. The tools we have to tailor this treatment are clinical evolution, the use of trough levels and lately pharmacokinetic (PK) programs.
OBJECTIVES: To evaluate the impact of a FVIII dose adjustment program using pharmacokinetic (PK) in daily routine practice: To analyse FVIII consumption in different treatment schedules (prophylaxis and demand) before and after the adjustment dose using PK programs.In subjects under prophylaxis scheme of treatment, to assess if this setting changes the annual rate of bleedings.To assess changes in quality of life after applying PK adjustment.
PATIENTS AND METHODS: Between January 2006 and December 2013, we performed pharmacokinetic studies in adult patients with severe hemophilia A (FVIII less than 1%) and no history of inhibitor that have changed from one FVIII product to a different one in our centre. The program is a Bayesian PK analysis. FVIII levels were determined by one-stage method. Samples were taken 30 minutes (recovery non used for PK), 6, 12, 24 and 48 hours after FVIII 50ui/kg infusion. After PK study, subjects on prophylaxis were evaluated every two months to adjust scheme of treatment to trough FVIII levels between 1 to 3% in absence of bleeding. After getting the established dose patients were reviewed every 6 months. Patients on demand were evaluated every 10 to 15 doses until they got 50 doses, and then every 12 months. Demographic and diagnostic data of patients were recorded for inclusion in the program. Information about FVIII consumption and bleeding events comes from patient diaries (PD) and records from Hospital Pharmacy Department. Quality of life (QoL) was analysed using the A 36 Hemophilia-QoL questionnaire (Spanish validated version). Our Centre Ethics Committee approved the project. Everything has been done according to the Declaration of Helsinki. Patients signed written informed consent.
RESULTS: Of the 16 patients included in the program only 14 have been evaluable. The excluded ones did not complete DP or CV properly. Mean age of the analysed patients was 31.7+/-9.4 years old. Mean body mass index was 25+/-2.7m2. 85% of patients suffer from haemophilic arthropathy according to Petterson Score (knee 57%, elbows 57%, ankles 85%). Four patients have been moved from plasma derived FVIII (pdFVIII) to other pdFVIII and 10 from pdFVIII to recombinant FVIII (rFVIII). Regarding to treatment regimens, 6 patients were changed from on demand to tertiary prophylaxis, 4 maintained their secondary prophylaxis and 4 continued on demand after the change of factor. The prophylaxis frequencies of infusions were every 48 hours in 2 patients, twice a week in 3 and 3 times a week in 5 of them. The mean volume of distribution, half-life (T1/2) and FVIII clearance (Acl) were 56.2±19 ml/kg, 12.9±5.9 h and 3.4±1.4 ml/kg. We found a correlation between age (p 0.03) and levels of vWF:RCo (p 0.02) with Acl. No correlation was found with body surface or VWF:Ag. Patients treated with pdFVIII have lower Acl and T1/2, 2.05 vs 3.9ml/kg (p 0.015) and 18.5 vs 10.6 h (p0.01) respectively. After trough level evaluation no increase of dose was necessary and only 2 patients decreased PK dose. The implementation of PK study has saved 20.3% of FVIII units in subjects on prophylaxis, mean and SD of pre and post PK FVIII consumption was 3137.3+/-387.9 IU/kg/year vs 2501.2+/-308.4 IU/kg/year (p 0.005). There was no change in the annual rate of bleedings after PK adjustment (2.33+/-1.2 vs 2+/-2.6, p 0.321). We found no changes in consumption in subject on demand after PK. There was an improvement in all domains of QoL test (p<0.0001) in subjects who changed from on demand to prophylaxis. This seems not to be related with PK but to prophylaxis that induces a decrease in the annual rate of bleeding of 78.5% (p 0.002). Two patients developed transitory low inhibitor titer after FVIII change with no clinical implications.
CONCLUSION: In our experience, the implementation of PK programs in the treatment of severe hemophilia A reduces FVIII consumption and optimizes schemes of prophylaxis. This saving does not modify bleeding rate or quality of life of patients.

Disclosures
No relevant conflicts of interest to declare.