Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients

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MARC

Abrantes, João A.Uppsala universitet,Institutionen för farmaceutisk biovetenskap (author)

Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients

Article/chapterEnglish2020

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2019-08-01
Ferrata Storti Foundation,2020
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LIBRIS-ID:oai:DiVA.org:uu-399996
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-399996URI
https://doi.org/10.3324/haematol.2019.217133DOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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Pharmacokinetic-based prophylaxis of replacement factor VIII products has been encouraged in the past years, but the exposure (factor VIII activity)-response (bleeding frequency) relationship remains unclear. The aim of this study was to characterize the relationship between factor VIII dose, plasma factor VIII activity, bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of factor VIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using nonlinear mixed effects modelling in NONMEM. In total, 183 patients (median age 22 years [range, 1-61]; weight 60 kg [11-124]) contributed with 1535 plasma factor VIII activity observations, 633 bleeds and 11 patient/study characteristics (median observation period 12 months [3.1-13.1]). A parametric repeated time-to-categorical bleed model, guided by plasma factor VIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability for the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research based on a post-hoc analysis of the LEOPOLD studies (ClinicalTrials.gov identifiers NCT01029340, NCT01233258 and NCT01311648).

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Hematologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Hematology hsv//eng
Hemophilia
clinical trials
population pharmacokinetics
recombinant factor VIII
repeated time-to-event

Added entries (persons, corporate bodies, meetings, titles ...)

Solms, Alexander (author)
Garmann, Dirk (author)
Nielsen, Elisabet I.,1973-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Farmakometri(Swepub:uu)elnie838 (author)
Jönsson, Siv,1963-Uppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)sivjonss (author)
Karlsson, MatsUppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)matskarl (author)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

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In:Haematologica: Ferrata Storti Foundation105:5, s. 1443-14530390-60781592-8721

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