Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9

Klein, Kerenaftali, Gueorguieva, Ivelina and Aarons, Leon (2012) Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9. Journal of Pharmacokinetics and Pharmacodynamics, 39 2: 147-160. doi:10.1007/s10928-011-9235-z


Author Klein, Kerenaftali
Gueorguieva, Ivelina
Aarons, Leon
Title Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9
Formatted title
Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9
Journal name Journal of Pharmacokinetics and Pharmacodynamics   Check publisher's open access policy
ISSN 1567-567X
1573-8744
Publication date 2012-04-01
Sub-type Article (original research)
DOI 10.1007/s10928-011-9235-z
Open Access Status Not yet assessed
Volume 39
Issue 2
Start page 147
End page 160
Total pages 14
Place of publication New York, NY, United States
Publisher Springer
Language eng
Abstract This study is to assess pharmacokinetic (PK) sampling time schedules and trial size requirements of drug-drug interaction (DDI) studies for CYP2C9, based on S-warfarin population PK models. S-warfarin plasma concentrations from eight DDI studies were utilized to develop S-warfarin population PK models. Optimal PK sampling times were obtained that minimized mean squared error of geometric mean of the area under the concentration-time curve (AUC(0-∞)). The powers and type I error rates of testing the equivalences of the geometric means of AUC(0-∞) only and AUC(0-∞) and maximum concentration (C (max)), jointly, were assessed via simulation for two-by-two cross-over designs. The results were compared to those from three bioequivalence sample size calculation methods. Two-compartment population PK models with first order absorption were established for non-Asian and Asian subjects. The optimal PK sampling times of size 17 per individual per period were found to be 0.0, 0.5, 1.0, 2.0, 4.0, 6.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 60.0, 72.0, 96.0, 120.0, 144.0 h post a single oral dose of 25 mg warfarin. For non-Asian subjects, the minimum numbers of subjects required per trial with the optimal PK sampling schedule to achieve 80% power and 5% type I error rate, ranged from 6 to 19 for the equivalence of AUC(0-∞) and C (max) jointly. It has been demonstrated that appropriately selected PK sampling time points can greatly increase the corresponding power of the study without increasing the number of subjects, especially when the true ratio is near the default bioequivalence boundary (0.8-1.25).
Formatted abstract
This study is to assess pharmacokinetic (PK) sampling time schedules and trial size requirements of drug-drug interaction (DDI) studies for CYP2C9, based on S-warfarin population PK models. S-warfarin plasma concentrations from eight DDI studies were utilized to develop S-warfarin population PK models. Optimal PK sampling times were obtained that minimized mean squared error of geometric mean of the area under the concentration-time curve (AUC 0-∞). The powers and type I error rates of testing the equivalences of the geometric means of AUC 0-∞ only and AUC 0-∞ and maximum concentration (C max), jointly, were assessed via simulation for two-by-two crossover designs. The results were compared to those from three bioequivalence sample size calculation methods. Two-compartment population PK models with first order absorption were established for non-Asian and Asian subjects. The optimal PK sampling times of size 17 per individual per period were found to be 0.0, 0.5, 1.0, 2.0, 4.0, 6.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 60.0, 72.0, 96.0, 120.0, 144.0 h post a single oral dose of 25 mg warfarin. For non-Asian subjects, the minimum numbers of subjects required per trial with the optimal PK sampling schedule to achieve 80% power and 5% type I error rate, ranged from 6 to 19 for the equivalence of AUC 0-∞ and C max jointly. It has been demonstrated that appropriately selected PK sampling time points can greatly increase the corresponding power of the study without increasing the number of subjects, especially when the true ratio is near the default bioequivalence boundary (0.8-1.25).
Keyword Warfarin
Drug-drug interactions
Pharmacokinetic modelling
Optimal design
Sample size
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Public Health Publications
 
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