Pharmacogenomic trial design: use of a PK/PD model to explore warfarin dosing interventions through clinical trial simulation.
OBJECTIVE
Variants of two genes, CYP2C9 and VKORC1, explain approximately one third of variability in warfarin maintenance dose requirements. However, the clinical utility of using this information in addition to clinical and demographic data ('pharmacogenomic-guidance') is unclear, as few comparative clinical trials have been conducted to date. The objective of this study was to explore the incremental effect of pharmacogenomic-guided warfarin dosing under various conditions using clinical trial simulation.


METHODS
We used an existing pharmacokinetic/pharmacodynamic model to perform clinical trial simulations of pharmacogenomic-guided versus standard of care warfarin therapy. The primary outcome was the percentage of patient time spent in therapeutic range over the first month of therapy. We assessed the influence of the frequency of INR monitoring, and the use of a loading dose and dose increase delay in patients with CYP2C9 variants.


RESULTS
Pharmacogenomic guidance resulted in a 3-4 percentage point absolute increase in time spent in therapeutic range over the first month of therapy compared with standard of care. The improvement in time in range was greater when the frequency of INR monitoring in both arms was assumed to be lower. The absolute difference increased to 6-8 percentage points with the use of a loading dose and dose increase delay in patients with a CYP2C9 variant.


CONCLUSIONS
Our initial results imply that pharmacogenomic-guided warfarin dosing may be more useful in settings with less intensive patient follow-up, and when adjustments are made for slower therapeutic response in patients with a CYP2C9 variant. Further pharmacokinetic/pharmacodynamic model development may be useful for warfarin pharmacogenomic trial design.
Salinger
David H
DH
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Shen
Danny D
DD
Thummel
Kenneth
K
Wittkowsky
Ann K
AK
Vicini
Paolo
P
Veenstra
David L
DL
D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D009010:Monte Carlo Method; D010597:Pharmacogenetics; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases