Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • 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
Comparisons of Analysis Methods for Assessment of Pharmacodynamic Interactions Including Design Recommendations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala Univ, Dept Pharmaceut Biosci, Box 591, SE-75124 Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala Univ, Dept Pharmaceut Biosci, Box 591, SE-75124 Uppsala, Sweden.ORCID iD: 0000-0002-3424-9686
2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 4, article id UNSP 77Article in journal (Refereed) Published
Abstract [en]

Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model. Simulated data were re-estimated using the MTP-GPDI model implemented in Bliss Independence or Loewe Additivity, or using a conventional model such as an Empirical Bliss Independence-based model or the Greco model based on Loewe Additivity. The GPDI model correctly characterized different PD interactions (antagonism, synergism, or asymmetric interaction), regardless of the underlying additivity criterion. The commonly used conventional models were not able to characterize asymmetric PD interactions, i.e., concentration-dependent synergism and antagonism. An optimized experimental design was developed that correctly identified interactions in ae<yen> 94% of the evaluated scenarios using the MTP-GPDI model approach. The MTP-GPDI model approach was proved to provide advantages to other conventional models for assessing PD interactions of anti-tubercular drugs and provides key information for selection of drug combinations for Phase 2b evaluation.

Place, publisher, year, edition, pages
2018. Vol. 20, no 4, article id UNSP 77
Keywords [en]
general pharmacodynamic interaction model, in vitro, multistate tuberculosis pharmacometric model, optimized design, pharmacodynamic interactions
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-386291DOI: 10.1208/s12248-018-0239-0ISI: 000436029800001PubMedID: 29931471OAI: oai:DiVA.org:uu-386291DiVA, id: diva2:1337553
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 115337Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2019-07-16Bibliographically approved

Open Access in DiVA

fulltext(1824 kB)45 downloads
File information
File name FULLTEXT01.pdfFile size 1824 kBChecksum SHA-512
142e47552e40d750ae829b00f15648b9e180dce14e5582e354a55e3de7137a564ef8b190cad3536fd95c8f8919a168e3f3fd2168efe652e162e493726ef8d42c
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Chen, ChunliNordgren, RikardSimonsson, Ulrika S. H.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
AAPS Journal
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 45 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: 55 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • 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