dc.contributor.author |
Xue, L |
en |
dc.contributor.author |
Holford, Nicholas |
en |
dc.contributor.author |
Ding, X-L |
en |
dc.contributor.author |
Shen, Z-Y |
en |
dc.contributor.author |
Huang, C-R |
en |
dc.contributor.author |
Zhang, H |
en |
dc.contributor.author |
Zhang, J-J |
en |
dc.contributor.author |
Guo, Z-N |
en |
dc.contributor.author |
Xie, C |
en |
dc.contributor.author |
Zhou, L |
en |
dc.contributor.author |
Chen, Z-Y |
en |
dc.contributor.author |
Liu, L-S |
en |
dc.contributor.author |
Miao, L-Y |
en |
dc.date.accessioned |
2017-06-09T02:07:42Z |
en |
dc.date.issued |
2017-04 |
en |
dc.identifier.citation |
British Journal of Clinical Pharmacology 83(4):823-835 Apr 2017 |
en |
dc.identifier.issn |
0306-5251 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/33382 |
en |
dc.description.abstract |
The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin.Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks.Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin.A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.publisher |
Blackwell Publishing Inc. |
en |
dc.relation.ispartofseries |
British Journal of Clinical Pharmacology |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0306-5251/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1111/bcp.13157 |
en |
pubs.issue |
4 |
en |
pubs.begin-page |
823 |
en |
pubs.volume |
83 |
en |
dc.description.version |
AM - Accepted Manuscript |
en |
dc.rights.holder |
Copyright: Blackwell Publishing Inc. |
en |
dc.identifier.pmid |
27763679 |
en |
pubs.end-page |
835 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
544185 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Pharmacology |
en |
dc.identifier.eissn |
1365-2125 |
en |
pubs.record-created-at-source-date |
2017-06-09 |
en |
pubs.dimensions-id |
27763679 |
en |