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Favorable Pharmacokinetic Characteristics of Extended-Half-Life Recombinant Factor VIII BAY 94-9027 Enable Robust Individual Profiling Using a Population Pharmacokinetic Approach

Solms, Alexander ; Iorio, Alfonso ; Ahsman, Maurice J. ; Vis, Peter ; Shah, Anita ; Berntorp, Erik LU and Garmann, Dirk (2020) In Clinical Pharmacokinetics 59(5). p.605-616
Abstract

Background: Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. Objective: The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. Methods: Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass... (More)

Background: Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. Objective: The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. Methods: Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass index, lean body weight (LBW), von Willebrand factor (VWF) level, and race were evaluated. A popPK model was developed and used to simulate pharmacokinetic endpoints difficult to observe from measured FVIII levels, including time to maintain FVIII levels above 1, 3, and 5 IU/dL after different BAY 94-9027 doses. Results: A one-compartment model adequately described BAY 94-9027 pharmacokinetics. Clearance and central volume of distribution were significantly associated with LBW; clearance was inversely correlated with VWF. Due to the monophasic pharmacokinetics and well-understood IIV sources, identification of patient pharmacokinetics was achievable with sparse blood sampling. Median predicted time to maintain FVIII levels > 1 IU/dL in patients aged ≥ 12 years ranged from 120.1 to 127.2 h after single BAY 94-9027 doses of 45‒60 IU/kg. Conclusions: This analysis evaluated the pharmacokinetics of BAY 94-9027 and its sources of IIV. Using the model, determination of individual patient pharmacokinetics was possible with few FVIII samples, and a sparse sampling design to support pharmacokinetic-guided dosing was identified.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Pharmacokinetics
volume
59
issue
5
pages
12 pages
publisher
Adis International
external identifiers
  • scopus:85075365418
  • pmid:31749076
ISSN
0312-5963
DOI
10.1007/s40262-019-00832-7
language
English
LU publication?
yes
id
a1c14615-4e69-4b14-b257-4a14a2fe660f
date added to LUP
2019-12-09 13:21:10
date last changed
2022-05-23 19:56:26
@article{a1c14615-4e69-4b14-b257-4a14a2fe660f,
  abstract     = {{<p>Background: Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. Objective: The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. Methods: Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass index, lean body weight (LBW), von Willebrand factor (VWF) level, and race were evaluated. A popPK model was developed and used to simulate pharmacokinetic endpoints difficult to observe from measured FVIII levels, including time to maintain FVIII levels above 1, 3, and 5 IU/dL after different BAY 94-9027 doses. Results: A one-compartment model adequately described BAY 94-9027 pharmacokinetics. Clearance and central volume of distribution were significantly associated with LBW; clearance was inversely correlated with VWF. Due to the monophasic pharmacokinetics and well-understood IIV sources, identification of patient pharmacokinetics was achievable with sparse blood sampling. Median predicted time to maintain FVIII levels &gt; 1 IU/dL in patients aged ≥ 12 years ranged from 120.1 to 127.2 h after single BAY 94-9027 doses of 45‒60 IU/kg. Conclusions: This analysis evaluated the pharmacokinetics of BAY 94-9027 and its sources of IIV. Using the model, determination of individual patient pharmacokinetics was possible with few FVIII samples, and a sparse sampling design to support pharmacokinetic-guided dosing was identified.</p>}},
  author       = {{Solms, Alexander and Iorio, Alfonso and Ahsman, Maurice J. and Vis, Peter and Shah, Anita and Berntorp, Erik and Garmann, Dirk}},
  issn         = {{0312-5963}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{605--616}},
  publisher    = {{Adis International}},
  series       = {{Clinical Pharmacokinetics}},
  title        = {{Favorable Pharmacokinetic Characteristics of Extended-Half-Life Recombinant Factor VIII BAY 94-9027 Enable Robust Individual Profiling Using a Population Pharmacokinetic Approach}},
  url          = {{http://dx.doi.org/10.1007/s40262-019-00832-7}},
  doi          = {{10.1007/s40262-019-00832-7}},
  volume       = {{59}},
  year         = {{2020}},
}