uu.seUppsala University Publications
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Modeling Exposure-Driven Adverse Event Time Courses in Oncology Exemplified by Afatinib
Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany.
Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany.
Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany.
Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany.
Show others and affiliations
2019 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 8, no 4, p. 230-239Article in journal (Refereed) Published
Abstract [en]

Models were developed to characterize the relationship between afatinib exposure and diarrhea and rash/acne adverse event (AE) trajectories, and their predictive ability was assessed. Based on pooled data from seven phase II/III clinical studies including 998 patients, mixed-effects models for ordered categorical data were applied to describe daily AE severity. Clinical trial simulation aided by trial execution models was used for internal and external model evaluation. The final exposure-safety model consisted of longitudinal logistic regression models with first-order Markov elements for both AEs. Drug exposure was included as daily area under the concentration-time curve (AUC), and drug effects on the AEs were correlated. Clinical trial simulation allowed adequate prediction of maximum AE grades and AE severity time courses but overestimated the proportion of AE-dependent dose reductions and discontinuations. Both diarrhea and rash/acne were correlated with afatinib exposure. The developed modeling framework allows a prospective comparison of dosing strategies and study designs with respect to safety.

Place, publisher, year, edition, pages
2019. Vol. 8, no 4, p. 230-239
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-392065DOI: 10.1002/psp4.12384ISI: 000476596700007PubMedID: 30681293OAI: oai:DiVA.org:uu-392065DiVA, id: diva2:1349803
Note

Matthias Freiwald and Mats O. Karlsson contributed equally

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved

Open Access in DiVA

fulltext(5734 kB)10 downloads
File information
File name FULLTEXT01.pdfFile size 5734 kBChecksum SHA-512
79b48e2c21578b537d5394e1bdc5f47dbbac6c8d8e3f96b57f00992d61bf677dce6c6811432982330be5913bd933b3242d83be03a9d12c02805610147b252e4e
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Karlsson, Mats O.

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
Pharmacology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar
Total: 10 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 17 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf