Pharmacology, Efficacy and Safety of a Triple-Secured Fibrinogen Concentrate in Children Less than or Equal to 12 Years with Afibrinogenaemia

Objective To date, the use of a fibrinogen concentrate (FC) administered in children with inherited fibrinogen deficiency is poorly documented. Treatment modalities may differ from those of adults. The aim of this study was to investigate the pharmacokinetics (PK), efficacy (bleeding/surgery) and safety of a triple-secured FC (FibCLOT, LFB, France) in young patients aged of 12 years or less. Methods This was a prospective, non-comparative, multicentre, phase 2–3 study. Estimated PK parameters were based on population PK modelling. Target fibrinogen levels were 1.2 and 1.0 g/L for major and minor events, respectively. In vivo recovery (IVR) was calculated at study entry to tailor the dose. Results Sixteen afibrinogenaemia patients were treated with FC: 12 included in the PK study (6 aged ≤ 6 years and 6 aged 7–12 years). IVR at 1 hour post-infusion (geometric mean [coefficient of variation]) was 1.91 [20%] mg/dL per mg/kg and results were similar between the two age groups (1.87 [14%]) and (1.96 [27%]) with no statistical differences. Estimated half-life (t 1/2) was 49.0 hours [12%] with no observed differences between groups (46.6 hours [10%] and 51.6 hours [12%]). Overall efficacy was rated as excellent/good in 96.9% of 32 bleeds and in 100% of 11 surgeries. Most of the events (39/43, 90.7%) were managed with one infusion. There was no serious adverse drug reaction. Conclusion Individually tailored dosing was efficacious in children who exhibited a lower IVR and shorter t 1/2 than those previously reported in adolescent and adult patients emphasising the importance of individualised dose optimisation.

RECOVERY TEST AND ITS ROLE IN ASSESSMENT OF LONG-TERM PROPHYLAXIS EFFECTIVENESS IN HEMOPHILIA A PATIENTS

Введение. Гемофилия А (ГФА) — сцепленное с Х-хромосомой рецессивное врожденное заболевание, обусловленное недостаточностью VIII фактора свертывания крови (FVIII). Главным признаком заболевания является склонность к кровотечениям. Клинические проявления ГФА, как правило, коррелируют с уровнем активности FVIII. Единственным эффективным лечением гемофилии в настоящее время является заместительная терапия препаратами дефицитного фактора. Материалы и методы. Проведен ретроспективный анализ результатов обследования 28 пациентов (14 детей в возрасте от 3 до 17 лет и 14 взрослых в возрасте от 21 до 57 лет) с тяжелой формой ГФА. Все пациенты находились на длительной профилактической терапии препаратами FVIII — как рекомбинантными, так и плазматическими. Для подбора оптимального режима профилактики пациенту с ГФА проводили тест восстановления (in vivo recovery) — определение активности FVIII в двух пробах крови; определяли также прирост показателя восстановления (incremental recovery), активированное частичное тромбопластиновое время и каолиновое время. Результаты. Проведена оценка теста восстановления фактора свертывания VIII при применении плазматических и рекомбинантного препаратов фактора VIII у пациентов с тяжелой гемофилией А; изучена корреляция теста восстановления с фармакодинамическими показателями, характеризующими состояние коагуляции. Заключение. Ввиду наличия внутрииндивидуальных и межиндивидуальных колебаний фармакокинетических показателей препаратов фактора свертывания VIII у пациентов с ГФА рекомендуется проведение теста восстановления как при назначении препарата фактора свертывания VIII, так и в процессе длительной профилактики с целью контроля за терапией и ее оптимизации в случае необходимости. Introduction. Hemophilia A (HРA) is a recessive X-linked congenital disease caused by the defi ciency of VIII coagulation factor (FVIII). Hemorrhagic tendency is the main sign of the disease. As a rule, clinical manifestations of HPA correlate with level of FVIII activity. At present time substitution therapy with medication of defi cit factor is the only eff ective treatment for hemophilia. Materials and methods. We performed a retrospective study analysis of 28 patients (14 children aged from 3 to 17 years and 14 adults aged from 21 to 57 years) examination with severe HРA. All patients received prolonged preventive therapy with recombinant factor VIII products. To select the optimal prophylaxis mode for patients with HPA we performed a recovery test (in vivo recovery), determination of FVIII activity in two blood samples, determined index of incremental recovery, activated partial thromboplastin time and kaolin time. Results. We assessed recovery test for coagulation factor VIII using plasma and recombinant factor VIII products in patients with severe haemophilia A and studied correlation of recovery test with pharmacodynamic parameters that characterized coagulation state. Conclusion. Due to intra-individual and inter-individual fl uctuations in pharmacokinetic parameters of recombinant factor VIII products in patients with HPA we recommend to perform a recovery test both at appointment of coagulation factor VIII product and also during of long-term prophylaxis for monitoring and optimization of therapy.

The In Vivo Recovery/Survivaland Pharmacokinetic Properties of Dexamethasone Sodium Phosphate Encapsulated in Autologous Erythrocytes

Introduction Crohn's disease and Ataxia Telangiectasia have been managed by extended release of dexamethasone from autologous red blood cells (RBC) with encapsulated dexamethasone sodium phosphate DSP. The EryDexSystem (EDS) is an automated system that loads RBC ex vivo using hypotonic opening of RBC followed by hypertonic resealing of the RBC and washing to prepare the DSP-RBC for infusion. In vivo, DSP is dephosphorylated within the RBC to dexamethasone which passively diffuses into the plasma. The objective of this two-phase study was to elucidate pharmacokinetics (PK) and in vivo 24-hour recovery of RBCs as well as RBC survival (T50) properties of RBC encapsulated DSP. Materials and Methods The study was conduct in two separate Phases, A and B. Phase A, the 24-hour RBC recovery and T50 survival phase, was designed as a randomized, concurrently controlled, single-blind, single-center study to determine the in vivo kinetics of EDS-processed autologous RBC. Healthy volunteer consenting subjects were randomized to receive autologous RBCs prepared using EDS and loaded with either 15-20mg DSP (Group 1A) or sham hypotonic saline (Group 2A). EDS prepared RBC were radiolabeled with 51-Cr following standard methods, and the in vivo labeled RBC followed over 49 days post infusion. The Phase B PK study was designed as an open-label, single-center Phase I study that evaluated two dose levels of DSP encapsulated in RBCs using the EDS. Healthy volunteer consenting subjects were randomized to receive autologous RBCs loaded with either 2.5-5 mg DSP (Group 1B) or 15-20 mg (Group 2B). Post-infusion plasma levels of dexamethasone were followed (over 42 days). Both studies conformed to the Declaration of Helsinki. Results Phase A: Ten subjects (3male; 7 female) were randomized to Groups 1A or 2A. The mean 24-hour RBC recovery ± SD [95% CL] was 77.9 ± 3.3% [73.8-81.9%] and 72.7 ± 10.5% [57.8-85.7%] for Groups 1A and 2A, respectively. The mean ± SD RBC life span in Group 1A was 84.3 ± 8.3 days with a mean T50 of 42.1 ± 4.1 [95% CL: 37.0, 47.3] days, whereas these values were 88.9 ± 6.2 days and 44.4 ± 3.1 [95% CL: 40.6, 48.3] days, respectively, in Group 2A. Sixteen (16) treatment-emergent adverse events (TEAEs) were recorded in Group 1A and 23 in Group 2A. All TEAEs were judged to be unlikely related to the treatment. Phase B: Eighteen subjects (12 male; 6 female) were randomized to Groups 2A and 2B. The actual DSP loading doses (mean ± SEM) were 4.2±0.27 mg and 16.9±0.90 mg. Release of dexamethasone from RBCs in vivo peaked at 1 hour after the end of IV infusion independent of the dose. A detailed summary of the PK parameters for dexamethasone for each treatment group is shown in Table 1. A sustained release of dexamethasone could be detected until 14 and 35 days after the single IV infusion ofEryDex in Group 1B and 2B, respectively. Six (6) TEAEs were reported in each group and were judged to be unlikely related to the study drug or procedure. Conclusion The results for the mean RBC in vivo recovery for DSP-loaded EDS-processed cells meet the FDA criteria for 24-hour RBC recovery of ≥ 75%, without adverse impact on the survival of EDS-processed RBCs. Most of the dexamethasone was rapidly released from the RBCs in vivo with a maximum peak occurring 1 hour after the end of the intravenous infusion, independent of the dose administered, but sustained release of dexamethasone could be detected until 14 and 35 days post infusion for the low and high doses, respectively. DSP-loaded autologous RBCs prepared using the EDS delivered a sustained dose of dexamethasone in vivo. Additional efficacy studies in targeted patient populations are indicated. Disclosures Szczepiorkowski: EryDel S.P.A.: Research Funding. Ferrari:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Benatti:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mambrini:EryDel S.P.A.: Employment, Equity Ownership. Hartman:EryDel S.P.A.: Consultancy. Dumont:EryDel S.P.A.: Research Funding.