Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING: Dutch Research Council (NWO)-ZonMw and Takeda.

Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A.

INTRODUCTION: Emicizumab prophylaxis improves coagulation function in congenital hemophilia A, regardless of inhibitor presence. We recently reported that emicizumab enhanced the coagulant potentials, ex vivo, in plasmas from patients with acquired hemophilia A (PwAHAs) at diagnosis. However, coagulant effects of emicizumab in PwAHAs during the clinical course remain unclear. AIM: To assess ex vivo coagulant effects of emicizumab in PwAHAs during the clinical course. METHODS/RESULTS: Blood samples were obtained from 14 PwAHAs on (median) days 0 and 6 during a severe-bleeding phase, and days 27 and 59 during a reduced-bleeding phase with elevated endogenous factor VIII (FVIII) and decreased inhibitor titers. If administered a single dose of 3 or 6 mg/kg, or two doses at 6 mg/kg followed by 3 mg/kg, estimated plasma emicizumab concentrations (10/5/2.5, 20/10/5, and 30/15/7.5 µg/mL on days 0-7/30/60, respectively) could be used to represent potential changes, based on the half-life (T 1/2: ∼30 days). Emicizumab concentrations that covered maximum plasma concentrations of each dosage were used for spiking on day 0. Ex vivo addition of estimated emicizumab to PwAHA's plasma containing endogenous FVIII and/or inhibitor, without and with recombinant (r)FVIIa administration during immunosuppressive therapy, increased the calculated Ad|min1| values, assessed by clot waveform analysis, and their coagulant potentials were below normal levels. Rotational thromboelastometry revealed that ex vivo emicizumab addition resulted in the further improvement of coagulant potentials in whole bloods when combined with rFVIIa administration. CONCLUSION: Based on ex vivo and in vitro data, emicizumab has the potential to be effective in clinical situations for PwAHAs.

Phase 4 Safety and Efficacy Study of Antihemophilic Factor (Recombinant) in Previously Treated Chinese Patients With Severe/Moderately Severe Hemophilia A.

Antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months' on-demand rAHF then 6 months' rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as "excellent"/"good" in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations.

BACKGROUND: The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. METHODS: FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). RESULTS: Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. CONCLUSION: BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.

A Practical, One-Clinic Visit Protocol for Pharmacokinetic Profile Generation with the ADVATE myPKFiT Dosing Tool in Severe Hemophilia A Subjects.

Standard pharmacokinetic (PK) assessments are demanding for persons with hemophilia A, requiring a 72-hour washout and 5 to 11 timed blood samples. A no-washout, single-clinic visit, sparse sampling population PK (PPK) protocol is an attractive alternative. Here, we compared PK parameters obtained with a traditional washout, 6-sampling time point PPK protocol with a no-washout, single-clinic visit, reverse 2-sampling time point PPK protocol in persons with severe hemophilia A (SHA) receiving ADVATE. A total of 39 inhibitor-negative males with SHA (factor VIII activity [FVIII:C] < 2%) were enrolled in a prospective sequential design PK study. Participants completed a washout, 6-sampling time point PPK protocol as well as a no-washout, reverse 2-sampling time point protocol, with samples taken during a single 3-hour clinic visit 24 hours post home infusion of FVIII and then 3 hours post infusion in clinic. FVIII:C levels were analyzed by one-stage and chromogenic assays; blood group and von Willebrand factor antigen (VWF:Ag) were determined; and PK parameters were analyzed using the ADVATE myPKFiT dosing tool. There was moderate to almost perfect agreement for the PK parameters obtained with the 2- and the 6- point PPK protocols using a one-stage FVIII:C assay and a substantial to almost perfect agreement using a chromogenic FVIII:C assay. Significant associations between specific PK parameters and blood group and VWF:Ag were observed. The no-washout, single-clinic visit, reverse 2-sampling time point PPK protocol can be used in the routine clinical setting since it demonstrates sufficient accuracy compared with the more demanding and less practical washout, 6-sampling time point PPK protocol in persons with SHA receiving ADVATE.

Cost of patients with hemophilia A treated with standard half-life or extended half-life FVIII in Spain.

BACKGROUND: In a real-world analysis (RWA) conducted in the United States (US), median international units (IUs) of extended half-life (EHL) recombinant coagulation factor VIII (rFVIII) dispensed were 10% to 45% greater than standard half-life (SHL) rFVIII. The mean IUs of each rFVIII dispensed quarterly were obtained from two databases (N = 776). METHODS: A probabilistic model in a 1-year time horizon was used in order to analyze the cost comparison of SHL and EHL rFVIII products in Spain. In this analysis, mean IUs were those of the RWA, and frequency of use and prices for each rFVIII were obtained from sales estimates based on Spanish sources (IQVIA; €, 2019). RESULTS: Data showed an average annual savings per patient of €11,227 for SHL rFVIII versus EHL rFVIII products, with a savings probability of 75.5%. The results were stable in the sensitivity analyses. Not switching treatment from SHL to EHL rFVIII resulted in greater savings per patient (€53,078), with a savings probability of 99.9%. Considering the frequency of rFVIII dispensation in the US, annual savings per patient would increase to €16,350 in Spain, with a savings probability of 79.9%. CONCLUSIONS: According to this model, use of SHL rFVIII versus EHL rFVIII products could lead to savings for the Spanish National Health System.

Pharmacodynamics of eftrenonacog-alfa (rFIX-Fc) in severe hemophilia B patients: A real-life study.

Eftrenonacog-alfa is a recombinant factor IX-Fc fusion protein increasingly prescribed in hemophilia B patients. We aimed to assess its pharmacodynamics (PD) in real-life setting via FIX activity measurement and thrombin generation assay (TGA). Sixty samples from 15 severe hemophilia B treated patients were collected at different time points. FIX activity was measured using product-specific one-stage clotting assay (reference method) and two chromogenic assays (CSA) (Biophen FIX and Rox FIX). TGA was triggered with 1 pM tissue factor. Five parameters were analyzed: lag time (LT), time to peak (TTP), peak height (PH), endogenous thrombin potential (ETP), and velocity. PD models were built to characterize their relationships with FIX activity, using mixed effects models. Mean trough FIX level was estimated at 4.64 (±1.50) IU/dl with a recovery at 0.78 (±0.16) IU/dl per 1 IU/kg injected dose. FIX activity ranged between 1 and 86 IU/dl with 21.5 IU/dl median value. Biophen FIX and Rox FIX allowed reliable measurements except in samples with FIX <20 IU/dl in which values were underestimated (delta >30%). PD models revealed that velocity was the most sensitive TGA parameter to FIX activity followed by PH, ETP, TTP and finally LT. Following FIX activity peak after eftrenonacog-alfa injection, velocity decreased first, followed by PH then ETP. Both CSA failed to accurately measure FIX in severe hemophilia B patients receiving eftrenonacog-alfa throughout the measuring range. TGA could be an additional valuable tool to evaluate hemostasis balance in treated patients.

Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

Biological mechanisms underlying inter-individual variation in factor VIII clearance in haemophilia.

Previous studies have highlighted marked inter-individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half-life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma-derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half-life for extended half-life (EHL-) FVIII products also demonstrates significant inter-patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half-life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter-individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half-life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo.

A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States.

BACKGROUND: Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices. OBJECTIVE: To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol. METHODS: Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII. RESULTS: Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged < 12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7, P < 0.001) and 20/56 PWHA had no bleeding events. There was also a 20.9% reduction in the mean days per week of factor administration (P < 0.001) after switching to prophylactic rurioctocog alfa pegol. For 47 PWHA who switched from SHL rFVIII, their weekly dose decreased from 109.8 to 100.6 IU per kg with rurioctocog alfa pegol (P = 0.094). The proportion of PWHA with good/complete treatment adherence increased from 68% (38/56) on any prior rFVIII to 80% (45/56) on rurioctocog alfa pegol. The most common reason PWHA switched to rurioctocog alfa pegol was to reduce treatment infusions. CONCLUSIONS: Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA. DISCLOSURES: This study was funded by Shire Development LLC, a Takeda company, Lexington, MA. Trio Health was involved in study design and acquisition, analysis, and interpretation of data and was funded by Shire Development LLC, a Takeda company. Aledort serves on the data and safety monitoring boards of Baxalta U.S. Inc., a Takeda company, and Octapharma; is chair of the scientific advisory board of Kedrion; and receives consultancy fees and honoraria from Baxalta U.S. Inc., a Takeda company. Milligan is an employee of Trio Health and reports research support from AbbVie, Gilead, Merck, Sanofi, and ViiV, unrelated to this study. Watt is an employee of Shire International GmbH, a Takeda company, and owns stock in the company. Booth was an employee of Baxalta U.S. Inc., a Takeda company, at the time of this study and owns stock in the company. Data from this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; April 23-28, 2018; Boston, MA; SETH (2018) Sociedad Espanola de Trombosis y Hemostasia-XXXIV Congreso Nacional; October 11-13, 2018; Grenada, Espana; and Blood 2018 Annual Scientific Meeting; October 21-24, 2018; Brisbane, Australia.

Pharmacokinetic and safety considerations when switching from standard to extended half-life clotting factor concentrates in hemophilia.

Introduction: Plenty of new FVIII/IX concentrates have been developed and entered the market of hemophilia treatment. Others are going to end the long/demanding procedures for approval. Changes of the FVIII molecule (single chain), pegylation of B-domain deleted FVIII, and fusion with Fc succeeded to improve the FVIII half-life, about 4 hours. Pegylation and fusion with albumin or Fc of rFIX caused a substantial increase of half-life, approximately 3-4 times that of FIX standard concentrates. Area covered: Extended Half-life concentrates may allow a longer time interval between the prophylaxis bolus, a feature very well accepted by young patients. Also, adherence of adolescents can be improved by these new, less demanding, concentrates. The immunogenicity of these new molecules is so far under post-marketing evaluation. The incidence of neutralizing antibodies is very low in previously treated patients, but the data on previously untreated patients are not yet assessed. The cost of some Extended Half-Life concentrates is higher than that of standard ones, and some concerns have been raised about the cost for public or private health care institutions. Expert opinion: An accurate evaluation of patients' needs, individual pharmacokinetics, and cost/effectiveness might allow a more appropriate usage of these new and expensive concentrates.

Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment that reverses dabigatran anticoagulation. Pharmacokinetics (PK) of idarucizumab have been described in healthy, elderly, or renally impaired (RI) volunteers, but PK data in patients are lacking. OBJECTIVES: This analysis describes the PK of idarucizumab and its target dabigatran in bleeding/surgical patients. PATIENTS AND METHODS: Results from the Reversal Effects of Idarucizumab on Active Dabigatran study, a prospective, multicenter, single-arm study demonstrated the reversal of dabigatran anticoagulation by idarucizumab in patients with uncontrollable bleeding (group A) or who needed urgent surgery (group B). Idarucizumab and unbound dabigatran concentrations, immunogenicity, and pharmacodynamics were assessed. RESULTS: Total and unbound dabigatran levels at baseline were 165 ng/mL vs 110 ng/mL and 103 ng/mL vs 69.5 ng/mL in group A and B patients, respectively. Maximum plasma concentrations and area under the curves (AUC0-24 ) of idarucizumab in group A vs B, respectively, were 24 900 nmol/L vs 25 000 nmol/L and 76 600 nmol/h/L vs 68 000 nmol/h/L. Idarucizumab AUC0-24 increased by 38% in mild, 90% in moderate, and 146% in severe RI patients vs normal renal function. Hepatic impairment or geographical region had no relevant effect on idarucizumab PK. Idarucizumab immediately decreased unbound dabigatran concentration (<20 ng/mL). A linear correlation was observed between unbound dabigatran and diluted thrombin time and ecarin clotting time. Antidrug antibody titers were low (1-64 at day 30; 0-16 at day 90) and had no impact on idarucizumab PK and pharmacodynamics. CONCLUSION: Idarucizumab PK in target patients was consistent with phase I data. Patient characteristics had no impact on PK, whereas RI increased the exposure of idarucizumab and dabigatran. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02104947.

Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data.

AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example. METHODS: We assessed 5 model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error percentiles. RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the prediction error [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios. CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualization is to include IOV in the generation of the EBEs but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

Pharmacokinetic-guided dosing of factor VIII concentrate in a morbidly obese severe haemophilia A patient undergoing orthopaedic surgery.

A 58-year-old morbidly obese male (body mass index: 38 kg/m2) with severe haemophilia A underwent total knee replacement surgery. Perioperatively, factor VIII (FVIII) levels were measured daily and maximum a posteriori (MAP) Bayesian estimation was used to calculate the individual pharmacokinetic (PK) parameters and doses required to obtain prescribed FVIII target levels. In the MAP Bayesian procedure, a population PK model was used in which PK parameters were normalised using body weight. In this specific case, ideal body weight was used to scale the PK parameters instead of actual body weight. Except for the preoperative FVIII level, adequate FVIII levels were achieved during the 10-day perioperative period. During follow-up visits, the knee prosthesis was reported to function adequately.

Laboratory assay measurement of modified clotting factor concentrates: a review of the literature and recommendations for practice.

Over the past several years, novel modified clotting factor concentrates (CFCs) have been introduced into practice and are now widely prescribed in the countries where they are licensed. These products allow for less frequent infusions of CFC, thereby providing improved convenience and/or higher trough levels. They have been extensively studied for prophylaxis, episodic treatment of bleeding and for surgical prophylaxis. One issue that has emerged regarding the clinical application of these products revolves around the measurement of infused CFC in the clinical coagulation laboratory. Recent studies have demonstrated significant problems with the measurement of correct FVIII/IX levels following infusion of novel CF VIII/IX concentrates. The source of this problem appears to be related to the tremendous variability of the APTT reagents that are used in the one-stage clotting assay, the most commonly used assay for determining factor levels. More specifically, the issue is related to the type of activator used in the reagents. Depending on the combination of the CFC and the APTT activator, the observed results may be either under- or overestimated to degrees that would be clinically relevant. Recommendations based on a review of published information regarding the potential for incorrect measurements of factor VIII/IX levels following infusion of recently developed, novel factor VIII/IX CFCs are presented for the clinician to use in clinical practice.

Safety of recombinant coagulation factors in treating hemophilia.

INTRODUCTION: During the last decade, new FVIII/IX concentrates have been developed for the treatment of patients affected by hemophilia A/B. Significant progress has been achieved regarding their half-life, but the old issue of immunogenicity and new concerns about safety need to be addressed. AREAS COVERED: After the implementation of virucidal methods, both plasma-derived and recombinant clotting factor concentrates achieved a very safe profile. The development of anti-FVIII antibodies is the major adverse event of replacement therapy with both FVIII concentrates. Furthermore, the new extended half-life concentrates, protein fused or pegylated, raised some concerns about their side effects. EXPERT OPINION: The treatment of hemophilia A with inhibitors by induction of immunotolerance and using by-passing concentrates, improved the quality of life of patients but did not allow them to have a life expectancy like that of patients without inhibitors. The new humanized monoclonal antibody (MAb) ACE910, mimicking FVIII function, seems to be able to reduce the bleedings of hemophilia A patients with inhibitors. The post-marketing surveillance will clarify if the adverse events observed during the phase III clinical trials and compassionate use were due to the association with a Prothrombin activated complex concentrate or to the prothrombotic effect of the drug itself.

Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study.

BACKGROUND: Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A. PATIENTS AND METHODS: Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD). RESULTS: Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold. CONCLUSION: Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes.

Factor VIII with a 237 amino acid B-domain has an extended half-life in F8-knockout mice.

Essentials Factor (F)VIII with an intermediate-length B-domain showed higher levels in murine gene therapy. FVIII with different B-domain lengths were analysed. FVIII variants with B-domains between 186 and 240 amino acids (aa) have extended half-life in mice. Reduced cell binding of FVIII with a 237aa B-domain may explain the extended half-life. SUMMARY: Background Factor VIII consists of the A1-domain, A2-domain, B-domain, A3-domain, C1-domain, and C2-domain. FVIII with an intermediate-length B-domain of 226 amino acids (aa) has previously been evaluated in murine gene therapy studies. Objective To characterize FVIII with intermediate-length B-domains in vitro and in vivo in F8-knockout (KO) mice. Methods and results FVIII molecules with B-domains of 186-240aa had longer half-lives in F8-KO mice than FVIII molecules with shorter or longer B-domains. FVIII with a B-domain containing the 225 N-terminal aa fused to the 12 C-terminal aa of the wild-type B-domain (FVIII-237) had a 1.6-fold extended half-life in F8-KO mice as compared with FVIII with a 21aa B-domain (FVIII-21). The in vitro and in vivo activity of FVIII-237 were comparable to those of FVIII-21, as was binding to von Willebrand factor. Cell binding to LDL receptor-related protein 1 (LRP-1)-expressing cells was markedly reduced for FVIII-237 as compared with FVIII-21, whereas the affinity for LRP-1 was not reduced in surface plasmon resonance (SPR) studies. FVIII-21 cell binding and internalization could be inhibited by a fragment consisting of the 226 N-terminal aa of the FVIII B-domain, and SPR analysis suggested that this B-domain fragment might bind with weak affinity to FVIII-21. Conclusion Reduced cell binding of FVIII-237 might explain the observed extended half-life in F8-KO mice. This may contribute to the increased FVIII levels measured in murine gene therapy studies using FVIII constructs with similar B-domain lengths.

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data.

INTRODUCTION: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. AIM: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. METHODS: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 µg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. RESULTS: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability. CONCLUSION: Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen.