Digitala Vetenskapliga Arkivet

Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
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
2019 (engelsk)Inngår i: CPT: Pharmacometrics & Systems Pharmacology, ISSN 2163-8306, Vol. 8, nr 12, s. 894-903Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.

sted, utgiver, år, opplag, sider
2019. Vol. 8, nr 12, s. 894-903
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-381217DOI: 10.1002/psp4.12464ISI: 000493314600001PubMedID: 31668021OAI: oai:DiVA.org:uu-381217DiVA, id: diva2:1302618
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2020-04-20bibliografisk kontrollert
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

Open Access i DiVA

fulltext(8028 kB)10 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 8028 kBChecksum SHA-512
f6747dafea9cea99e403f0e8ed8a2f7f54ea5973b2a01afcb7865c3584d4fdda81556b9748fc810f4a641e53a0ca45fd46d6ce94ddfaf9e6f29d52c5a19c6bc8
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Abrantes, João A.Nielsen, Elisabet I.Jönsson, SivKarlsson, Mats
Av organisasjonen

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 10 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 422 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf