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Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Bayer, Berlin, Germany.
Bayer, Wuppertal, Germany.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Vise andre og tillknytning
(engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-381217OAI: oai:DiVA.org:uu-381217DiVA, id: diva2:1302618
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-04-05
Inngår i avhandling
1. Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
Åpne denne publikasjonen i ny fane eller vindu >>Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.

A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.

High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.

The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.

Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.

In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 70
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 270
Emneord
Bayesian forecasting, coagulation factor VIII, dose adaptation, hemophilia/haemophilia A, inter-occasion variability, NONMEM, pharmacodynamics, pharmacokinetics, pharmacometrics, therapeutic drug monitoring
HSV kategori
Forskningsprogram
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-381218 (URN)978-91-513-0631-5 (ISBN)
Disputas
2019-05-29, B41, Biomedicinskt centrum, Husargatan 3, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2019-05-06 Laget: 2019-04-05 Sist oppdatert: 2019-06-17

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Abrantes, João A.Nielsen, Elisabet I.Jönsson, SivKarlsson, Mats

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