scholarly journals Combining factor VIII levels and thrombin/plasmin generation: a population pharmacokinetic‐pharmacodynamic model for patients with hemophilia A

2021 ◽  
Author(s):  
Laura H. Bukkems ◽  
Lars L. F. G. Valke ◽  
Wideke Barteling ◽  
Britta A. P. Laros‐van Gorkom ◽  
Nicole M. A. Blijlevens ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Pharmacodynamic Model ◽  
Population Pharmacokinetic

scholarly journals A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

2020 ◽  
Vol 120 (05) ◽  
pp. 747-757
Author(s):  
Laura H. Bukkems ◽  
Jessica M. Heijdra ◽  
Mary Mathias ◽  
Peter W. Collins ◽  
Charles R. M. Hay ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Factor Viii ◽  
Clinical Data ◽  
Hemophilia A ◽  
Clinical Trial Data ◽  
Recombinant Factor Viii ◽  
Percentage Error ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Fc Fusion Protein

Abstract Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.

scholarly journals Population Pharmacokinetic Modeling and Simulation of Recombinant Single-Chain Factor VIII (r VIII-SingleChain) in Patients with Hemophilia a

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2814-2814
Author(s):  
Ying Zhang ◽  
Tharin Limsakun ◽  
Debra M. Bensen-Kennedy ◽  
Alex Veldman ◽  
Zhenling Yao
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Fviii Activity ◽  
Dosing Regimens ◽  
Trough Levels ◽  
Plasma Activity

Abstract Introduction: Hemophilia A is a rare but serious X-linked recessive bleeding disorder that affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. rVIII-SingleChain is a proprietary, lyophilized formulation of clotting factor VIII (FVIII) produced by recombinant technology. As part of the clinical development of rVIII-SingleChain, a population pharmacokinetic (PK) analysis was undertaken, utilizing data from Study CSL627_1001 in subjects with hemophilia A, with the objectives of (a) characterizing the PK of rVIII-SingleChain at a population level, (b) assessing the ability of various patient characteristics (e.g., von Willebrand factor, VWF) to describe variability in the PK parameters, and (c) enable population-based simulations of rVIII-SingleChain dosing regimens that may provide improved prophylaxis coverage compared with octocog alfa (Advate®). Methods: Twenty-seven male subjects (aged 19-60 years) enrolled in Study CSL627_1001 (Part 1) received a single 50 IU/kg IV infusion of Advate®, followed by a single 50 IU/kg IV infusion of rVIII-SingleChain, with a minimum 4-day washout period. Plasma PK samples (for the determination of FVIII activity) were collected over 72 hours for both Advate® and rVIII-SingleChain (at pre-specified time points) and were measured by a validated chromogenic assay. Population PK models were developed separately for rVIII-SingleChain and Advate®, using the NONMEM 7 with FOCEI method. Various covariates, including VWF, body weight, and effect of age on clearance (CL) and volume of distribution were tested. Bootstrap and visual predictive check (VPC) were used for model evaluation. Simulations of different dosing regimens were performed to evaluate the FVIII activity plasma exposure profiles that may provide improved prophylaxis coverage. Results: A two-compartmental model with first-order elimination was developed to describe FVIII plasma activity data for both rVIII-SingleChain and Advate®. VWF was found to be a significant covariate influence on FVIII plasma activity CL, whilst body weight influenced both CL and volume of distribution in the central compartment. Population parameter estimates indicated a lower CL (2.02 vs 2.49 dL/h) and longer half-life (13.1 vs 9.3 h) for rVIII-SingleChain compared with Advate®. The results of bootstrap and VPC implied that the model was stable, and the parameters were estimated with good precision. PK simulations indicated that rVIII-SingleChain, at the same doses and frequencies, resulted in higher FVIII plasma activities throughout the dosing period, as reflected in higher area-under-the-curve (AUC). The dosing regimens for the simulations were designed based on the dosing recommendations of the Advate® label and rVIII-SingleChain phase III study. The results showed that rVIII-SingleChain provided a higher percentage of subjects with trough levels of at least 1% FVIII plasma activity, compared with Advate® at the same dosing regimen. Every 3 days dosing at 40-50 IU/kg rVIII-SingleChain was predicted to achieve similar prophylaxis protection compared with Advate® every 2 days (i.e., about 90% of subjects with trough levels of at least 1% FVIII plasma activity). In addition, 73-90% of subjects were predicted to achieve trough levels of at least 1% FVIII plasma activity with twice weekly dosing (4- and 3-day schedule) at 50 IU/kg rVIII-SingleChain, compared with 65-80% of subjects dosed with Advate® using the same regimen. Conclusion: The population model shows that rVIII-SingleChain has a longer half-life, lower CL and higher AUC compared with Advate®. Simulations demonstrated that rVIII-SingleChain resulted in higher trough concentrations when compared with Advate®, indicating the possibility of greater prophylaxis coverage. Disclosures Zhang: CSL Behring: Employment. Limsakun:CSL Behring: Employment. Bensen-Kennedy:CSL Behring: Employment. Veldman:CSL Behring GmbH: Employment. Yao:CSL Behring: Employment.

scholarly journals A Method for Deriving Pharmacokinetic Constants for Factor VIII and IX from Limited Blood Sampling

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3501-3501 ◽  
Author(s):  
Miguel Antonio Escobar ◽  
Daniel Preston Bond ◽  
Madeline Cantini ◽  
Krishna Cannon
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Research Funding ◽  
Decay Constant ◽  
Hemophilia A ◽  
Health Science ◽  
Blood Sampling ◽  
Population Pharmacokinetic ◽  
Viii And Ix ◽  
Trough Levels

Abstract Introduction The treatment of hemophilia A and B is based on the replacement of the deficient factor dosed by weight. However, dosing for hemophilia treatment has been arrived at by empiric assessment, essentially "trial and error" based on the pharmacokinetics (PK) of the factors and the characteristics of the replacement product. In the last decade clinical pharmacokinetics has gained popularity in hemophilia so that factor dosage can be adjusted according to the requirement of the individual patient. Factor-specific population pharmacokinetic models have been developed for individualized treatment of patients with hemophilia A and B. The math modeling technique presented in this project relies on minimal blood sampling to derive the constants necessary to predict the peak and trough levels within the commonly excepted error bounds. Methods Data that included FVIII, FIX levels and weight were obtained retrospectively from severe hemophilia A and B adult patients and approved by the ethics committee of the University of Texas Health Science Center. A single compartment decay model equation was used in both a custom iOS application and an Excel spreadsheet to calculate the decay constant between any 2 points on a decay curve. Using this local constant as the half-life in the standard decay equation allowed the calculation of the peak at time = 0. This peak combined with dosing information and the subject's weight allowed the calculation of the Recovery. These 2 constants in the equation: Level=(dose*Recovery/weight)*0.5^(time/half-life) allowed the calculation of the level at any point on the curve. Using this method on several example datasets showed that the model is reasonably able to predict peak and trough levels for both factor VIII and IX. Because of the time dependent nature of the local decay constant, better results are obtained using data points after the first half of the expected half-life. This method can also be used to predict steady state levels, peaks and troughs for any prophylaxis schedule. Conclusion Appropriate dosing of factor VIII or IX is at best an approximate calculation. The method described in this publication generates a math model that is generally as accurate as a multiple sample PK study with far fewer blood samples taken. Clinical applications of this model can be utilized to predict factor levels after a single infusion of factor VIII/IX in adults that are treated on-demand or prophylaxis. It can also be utilized in individuals that are infusing extended half-life products or in the surgical setting. Disclosures Escobar: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Pfizer: Consultancy, Research Funding. Cantini:Pfizer: Research Funding. Cannon:Pfizer: Research Funding.

scholarly journals Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model

Haematologica ◽  
2020 ◽  
pp. haematol.2019.241554 ◽  
Author(s):  
Andreas Tiede ◽  
Faraizah Abdul Karim ◽  
Victor Jiménez-Yuste ◽  
Robert Klamroth ◽  
Sandra Lejniece ◽  
...  
Keyword(s):  
Factor Viii ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Hemophilia A ◽  
Bleeding Risk ◽  
Population Pharmacokinetic ◽  
Severe Hemophilia ◽  
Factor Viii Activity

scholarly journals A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

Haematologica ◽  
2016 ◽  
Vol 101 (10) ◽  
pp. 1159-1169 ◽  
Author(s):  
H. Hazendonk ◽  
K. Fijnvandraat ◽  
J. Lock ◽  
M. Driessens ◽  
F. van der Meer ◽  
...  
Keyword(s):  
Factor Viii ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Hemophilia A ◽  
Population Pharmacokinetic

T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

1996 ◽  
Vol 76 (01) ◽  
pp. 017-022 ◽  
Author(s):  
Sylvia T Singer ◽  
Joseph E Addiego ◽  
Donald C Reason ◽  
Alexander H Lucas
Keyword(s):  
T Lymphocytes ◽  
Factor Viii ◽  
Cellular Proliferation ◽  
Mononuclear Cells ◽  
Hemophilia A ◽  
Normal Subjects ◽  
Normal Male ◽  
Cell Fractionation ◽  
Severe Hemophilia ◽  
Human Factor Viii

SummaryIn this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production

Treatment of Hemophilia A with a Highly Purified Factor VIII Concentrate Prepared by Anti-FVIIIc Immunoaffinity Chromatography

1992 ◽  
Vol 67 (01) ◽  
pp. 019-027 ◽  
Author(s):  
Joseph E Addiego ◽  
Edward Gomperts ◽  
Liu Shu-Len ◽  
Patricia Bailey ◽  
Suzanne G Courter ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Virus Transmission ◽  
Human Albumin ◽  
Immunoaffinity Chromatography ◽  
Exchange Chromatography ◽  
Pharmacokinetic Studies ◽  
Enveloped Viruses ◽  
Clinically Significant ◽  
Detergent Mixture

SummaryTo reduce the risk of pathogenic virus transmission associated with the therapeutic administration of plasma-derived antihemophilic factor (FVIIIc), a process utilizing anti-FVIIIc immunoaffinity chromatography to isolate FVIIIc has been developed. In addition, the starting cryoprecipitate solution has been treated with an organic solvent/detergent mixture to inactivate lipid-enveloped viruses. A final ion exchange chromatography step is used to further remove contaminants, e.g., anti-FVIIIc antibody, potentially leached with FVIIIc during the immunoaffinity step. The purified FVTII is stabilized for lyophili-zation and storage by the addition of human albumin. The monoclonal anti-FVIIIc antibody used in the immunoaffinity step of the process is not detectable in the final preparation. Viral reduction studies performed at specific steps of the process demonstrate that 11 logs of human immunodeficiency virus (HIV) and greater than 4-5 logs of other lipid-enveloped viruses are inactivated within the first 30 s of exposure to the solvent/ detergent mixture and 4-5 logs of various model viruses, e. g. Endomyocarditis virus (EMC), are physically removed during washing of the immunoaffinity column. The lyophilized product is reconstituted using sterile water in a matter of seconds.The pharmacokinetics of Hemofil® M were compared to those obtained using a standard heat-treated concentrate (Hemofil® CT) in five severe factor VIII deficient hemophiliacs in a randomized, cross-over study. No statistically significant differences were observed in mean half life (p >0.6) or median recovery (p = 0.4) between the two preparations. No clinically significant adverse effects were observed in patients receiving either FVIII preparation.In addition, 43 patients at 18 different centers underwent pharmacokinetic studies, with a nominal dose of 50 u/kg FVIIIc Hemofil® M. The mean recovery was 103.6%, and the t 1/2 was 14.6 h. The recovery of FVIII in this group was as expected, providing an increase of assayed FVIII of approximately 2% per unit of FVTII/kg infused.Clinical trials using Hemofil® M have been initiated in 124 hemophilia A patients. The safety and efficacy of Hemofil® M has been established. To date, 0 of 60 patients tested have seroconverted to HIV. None of the previously untreated patients show clinical or laboratory evidence of Non-A, Non-B hepatitis (NANB), with 21 patients remaining negative as far as presence of antibodies to the Hepatitis C virus (a-HCV negative) at least 6 months after the initial infusion. There is no evidence of neoantigenicity, evidenced by seroconversion to murine antibody. An 8.7% (2 of 23) prevalence of anti-FVIIIc inhibitor development has been observed in previously untreated patients with FVIIIc⩽3%, receiving only the monoclonally purified solvent/ detergent treated FVIII concentrate while on study and on poststudy surveillance. All patients demonstrated clinical hemostasis following product use for either on demand bleeding or surgical prophylaxis.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

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