Population pharmacokinetics of a new long-acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B

Essentials The new recombinant factor IX (FIX) albumin fusion protein (rIX-FP) has a prolonged half-life. A population pharmacokinetic (PK) model was based on FIX activity levels of hemophilia B patients. The model was used to simulate different dosing scenarios of rIX-FP to help guide dosing. The population PK model supported prolonged dosing of rIX-FP with intervals of up to 2 weeks. Click to hear Prof.Makris's presentation on new treatments in hemophilia SUMMARY: Background The recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP; Idelvion® ) exhibits a longer half-life than plasma-derived factor IX (FIX) and the commercially available recombinant FIX products. Objectives (i) Characterize the population pharmacokinetics (PK) of rIX-FP in hemophilia B patients, (ii) identify covariates that are potential determinants of rIX-FP PK variability and (iii) simulate different dosing scenarios of rIX-FP following single and steady-state dosing. Patients/Methods A population PK model was developed based on FIX activity levels of 104 patients who had received treatment with rIX-FP. Patients were aged 1-65 years with FIX activity ≤ 2 IU dL-1 . PK sampling was performed for up to 14 days (336 h). Results Simulation of a single intravenous infusion of rIX-FP (25-75 IU kg-1 ) predicted that the median trough exogenous FIX activity levels would remain > 5 IU dL-1 for up to 16 days in adolescents/adults aged ≥ 12 years, up to 12 days in children aged 6 to 5 IU dL-1 for the duration of the dosing interval for the 25, 35 and 40 IU kg-1 weekly regimens and for 75 IU kg-1 every 14 days in adolescents/adults, and for the 35 and 40 IU kg-1 weekly regimens in children. Conclusion The population PK model developed here correlates well with observed clinical data and supports prolonged dosing of rIX-FP with intervals of up to 2 weeks

Histopathological modifications in blood-induced haemophilic artropathy

Haemarthrosis triggers haemophilic arthropathy (HA), involving mainly the larger joints. Mechanisms and pathways of blood-induced joint damage are still not completely clear. The molecular triad OPG/RANK/RANKL tightly controls the bone turnover and any change in the balance between OPG and RANKL leads to bone pathological conditions. The aim of this study was to evaluate the expression of RANK/RANKL/OPG system in synovial tissue of haemophilic patients (pts) with severe HA, compared to osteoarthritic (OA) pts. Synovial biopsies from 20 HA pts and from 16 OA pts, obtained during arthroplasty of the knee, were routinally processed for light microscopy. The severity of HA was evaluated according to i) Ultrasonography (US) score, ii) World Federation of Haemophilia orthopaedic joint scale (WFH) and iii) radiographic Petterson method. Synovial sections were stained with H&E to evaluate pathological changes. The expression of RANK, RANK-L, OPG was examined by immunohistochemistry. Moreover, serum levels of sRANKL and OPG from 67 HA pts and 30 controls were measured by ELISA assay. The mean US, WFH and Pettersson score in HA pts were 11(range 0-21 with cut off>5), 39,5 (range:12-57), and 10,4 points (range: 6-12), respectively. Microscopically, the synovium from HA pts showed a large amount of intra- and extracellular haemosiderinic deposits. The lining layer showed mild proliferation and in the sublining area the vessels showed thickened wall, due to a local and chronic inflammatory stimuli. A lower expression of OPG was found in HA synovium compared to OA. RANK and RANK-L positivity was strongly expressed in the lining and sublining both in HA and OA synovial tissue. Serum levels of sRANKL and OPG resulted lower than in controls. Our preliminary data show that, in HA pts, the synovium highly expressed RANK and RANKL, whereas OPG positivity decreased, suggesting an osteoclastic activation. Tissue expression of OPG correlates with serum level of this protein in HA pts and with severity of HA, as assessed by US score

The expert in hemostasis and thrombosis in the Italian health system: role and requirements for a specific clinical and laboratory expertise

Hemorrhagic and thrombotic diseases are highly heterogeneous disorders that may affect a large proportion of the population, as in the case of patients taking antithrombotic drugs. The appropriate management of such conditions requires the availability of specific diagnostic assays, together with knowledge of the possible clinical syndromes and of their appropriate treatment. This can only be achieved through second-level specialized laboratories supervised by trained personnel. Such diagnostic and therapeutic organization is not widely available in Italy except in a very limited number of those large hospitals that are centers of excellence on a national scale. Increasing the availability of such resources would be of great benefit to patients, and could also be cost-effective for the national healthcare system. This document is promoted by the Italian Society for the Study on Hemostasis and Thrombosis (SISET) and by the main Italian scientific societies involved in the field during the years 2011-2012. It aims to identify the level of scientific and professional training required to define a physician as a Hemostasis and Thrombosis Expert, graded according to the levels of skill required for different clinical settings

F9 Missense mutations impairing factor ix activation are associated with pleiotropic plasma phenotypes

Background: Circulating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in haemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels. Objectives: To investigate i) expression of a complete panel of missense mutations at FIX activation sites and ii) contribution of F9 genotypes on the FIX pharmacokinetics (PK). Methods: FIXag and activity assays in plasma and after recombinant expression of FIX variants. Analysis of infused FIX PK parameters in patients (n=30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42). Results: The variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants result in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. PK analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 hrs, 95% CI 44.3-114.5) in patients (n=7) with the R191/R226 substitutions, which in regression analysis were independent predictors (β coefficient 0.699, p=0.004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX. Conclusions: FIXag levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients’ phenotypes and substitutive treatment

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease : Results from 3WINTERS-IPS, an international and collaborative cross-sectional study

Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels <20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.Peer reviewe

A calculator program for clinical application of the Bayesian method of predicting plasma drug levels

A pharmacokinetic program that allows individualization of drug dosage regimens through the Bayesian method is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based upon the one-compartment open model with either instantaneous or zero-order absorption. Individualized estimation of the patient's kinetic parameters (clearance and volume of distribution) is performed by analyzing the plasma levels measured in the patient as well as considering the population data of the drug. After estimating the individual kinetic parameters by the Bayesian method, the program predicts the dosage regimen that will elicit the desired peak and trough plasma levels at steady state. For comparison purposes, the least-squares estimates for clearance and volume of distribution are calculated, and dosage prediction can also be made on the basis of the least-squares estimates. The least-squares estimates can be used to calculate population pharmacokinetic parameters according to the Standard Two-Stage method.Several examples of clinical use of the program are presented. The examples refer to patients with classic hemophilia who were treated with Factor VIII concentrates. In these patients, the Bayesian kinetic parameters of Factor VIII have been estimated through the calculator program. The Bayesian parameter estimates generated by the HP-41 have been compared with those determined by a Bayesian program (ADVISE) designed for microcomputers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25858/1/0000421.pd

The History of Clotting Factor Concentrates Pharmacokinetics

Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy