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Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach
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- Brekkan, Ari (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Lledo-Garcia, Rocio (author)
- UCB Pharm, Slough, Buckinghamshire, England.
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- Lacroix, Brigitte (author)
- UCB Pharm, Braine Lalleud, Belgium.
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- (creator_code:org_t)
- Springer, 2024
- 2024
- English.
- In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer. - 1567-567X .- 1573-8744. ; 51:1, s. 65-75
- Journal article (peer-reviewed)
Abstract
Subject headings
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- Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Anti-drug antibody formation
- Certolizumab pegol
- anti-TNF
- hidden-Markov model
Publication and Content Type
- ref (subject category)
- art (subject category)
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