Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

Björkman, Sven; Åhlén, Victor

doi:10.1007/s00228-012-1211-z

Cited by 33 publications

(64 citation statements)

References 35 publications

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“…The small IIV and residual errors indicate that the model described the data adequately and rFIXFc pharmacokinetics do not vary substantially among patients. The estimated IOVs for CL and V 1 were 15.1 and 17.4 %, respectively, similar to those reported for plasma-derived FIX (15 % for CL and 12 % for V 1 ) [12]. The small and randomly distributed IOVs on CL and V 1 indicate that rFIXFc pharmacokinetics are relatively stable at different occasions.…”

Section: Discussionsupporting

confidence: 81%

“…For a typical 73 kg patient, V 1 for rFIXFc at 71.4 dL is larger than the plasma volume, which is around 30 dL for a typical adult, indicating that rFIXFc is not limited in the plasma for the initial distribution phase after intravenous administration, similar to that of FIX, which is known to bind to collagen IV in the subendothelium [26]. The IIVs for CL and V 1 were low to moderate at 17.7 and 21.7 %, respectively, which are consistent with those reported for plasma-derived FIX (23 % for CL and 19 % for V 1 ) [12]. Residual errors were small with a proportional error of 10.6 % and additive error of 0.24 IU/dL.…”

Section: Discussionsupporting

confidence: 80%

“…The corrected FIX activities were recorded as the dependent variable (DV) in the population pharmacokinetic dataset. Similar baseline and residual activity corrections were reported previously for the pharmacokinetic analyses of other FIX products [12–15]. …”

Section: Methodssupporting

confidence: 77%

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Population Pharmacokinetic Modelling of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Patients with Haemophilia B

Diao

Ludden

et al. 2014

Clin Pharmacokinet

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Background and ObjectivesRecombinant factor IX Fc fusion protein (rFIXFc) is a clotting factor developed using monomeric Fc fusion technology to prolong the circulating half-life of factor IX. The objective of this analysis was to elucidate the pharmacokinetic characteristics of rFIXFc in patients with haemophilia B and identify covariates that affect rFIXFc disposition.MethodsPopulation pharmacokinetic analysis using NONMEM® was performed with clinical data from two completed trials in previously treated patients with severe to moderate haemophilia B. Twelve patients from a phase 1/2a study and 123 patients from a registrational phase 3 study were included in this population analysis.ResultsA three-compartment model was found to best describe the pharmacokinetics of rFIXFc. For a typical 73 kg patient, the clearance (CL), volume of the central compartment (V1) and volume of distribution at steady state (Vss) were 2.39 dL/h, 71.4 dL and 198 dL, respectively. Because of repeat pharmacokinetic profiles at week 26 for patients in a subgroup, inclusion of inter-occasion variability (IOV) on CL and V1 were evaluated and significantly improved the model. The magnitude of IOV on CL and V1 were both low to moderate (<20 %) and less than the corresponding inter-individual variability. Body weight (BW) was found to be the only significant covariate for rFIXFc disposition. However, the impact of BW was limited, as the BW power exponents on CL and V1 were 0.436 and 0.396, respectively.ConclusionThis is the first population pharmacokinetic analysis that systematically characterized the pharmacokinetics of long-lasting rFIXFc in patients with haemophilia B. The population pharmacokinetic model for rFIXFc can be utilized to evaluate and optimize dosing regimens for the treatment of patients with haemophilia B.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-013-0129-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 80%

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Population Pharmacokinetic Modelling of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Patients with Haemophilia B

Diao

Ludden

et al. 2014

Clin Pharmacokinet

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“…Therefore, as an individual ages the PK profile for that individual can change, suggesting a need for repeated PK assessments to optimize individualized therapy. It has however been argued that the need for PK monitoring of FIX to tailor dosing may be limited, but even these experts recommend monitoring children, patients who do not respond to standard dosing and patients who switch from a plasma-derived to a recombinant FIX [48]. In the case of HA, however, there is strong evidence to suggest age related changes in the half-life which in turn affect the prophylactic dose required to maintain the desired trough level [49].…”

Section: Personalized Dosing Of Coagulation Factorsmentioning

confidence: 95%

Personalized Approaches to the Treatment of Hemophilia A and B

et al. 2015

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The recognition that individuals respond differently to the same medication is not new and dates almost to the founding of western medicine. In the last century it came to be recognized that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and effectiveness. Nonetheless, it has been challenging to integrate pharmacogenetic approaches in the routine practice of medicine as the identification of biomarkers is difficult due to the inherent complexity of biological systems. Here, we present potential applications of pharmacogenetics in managing hemophilia A and B. We discuss how predicting and circumventing immunogenicity, an important impediment to treating hemophilia patients, particularly lends itself to a pharmacogenetic approach. In addition, we discuss new trends toward personalizing the management of hemophilia in clinical settings.

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“…A PopPK 2-compartment model of rFVIII concentrate was developed by Bjorkman [83] from the 236 PK of 152 patients to investigate the relationship between the age and body weight. Afterwards, a PopPK 3-compartmet model of rFIX was developed [84] for tailoring prophylaxis in haemophilia B patients according to their FIX trough level. Also, a PopPK 3-compartment model of high-purity and monoclonal purified pdFIX concentrates was developed, merging the data of 5 different single dose PK studies conducted in a small cohort of patients [85].…”

Section: Population Pharmacokineticsmentioning

confidence: 99%

The History of Clotting Factor Concentrates Pharmacokinetics

Morfini¹

2017

JCM

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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.

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Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

Cited by 33 publications

References 35 publications

Population Pharmacokinetic Modelling of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Patients with Haemophilia B

Population Pharmacokinetic Modelling of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Patients with Haemophilia B

Personalized Approaches to the Treatment of Hemophilia A and B

The History of Clotting Factor Concentrates Pharmacokinetics

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