Theory based PK-PD of S- and R-warfarin: influence of body size, composition and genotype
Ling Xue (1), Nick Holford (2), Liyan Miao (1)
(1) Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, China (2) Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand
Objectives: 1) Apply a theory based mechanistic model to describe the PK and PD of S- and R-warfarin [1] 2) To explore the effect of body size, body composition [2] and genotype on warfarin PKPD parameters.
Methods: Blood samples for S- and R-warfarin were taken in addition to measurement of INR from 264 patients. Total (bound plus unbound) concentrations were measured by UPLC/MS-MS. Genotypes were measured using pyrosequencing of DNA extracted from blood leukocytes. A sequential population PK parameter with data method was used to describe INR. The PKPD model assumed an immediate effect on the turnover of prothrombin complex activity (PCA). INR was assumed to be equal to 1/PCA. Data were analyzed using NONMEM.
Results: The warfarin PK model had first-order input, one compartment distribution and first-order elimination. The input was assumed to be the same for both enantiomers with enantiomer specific estimates for CL and V. Theory based allometry and normal fat mass described size associated differences. CYP2C9 *1/*3 genotype had CL reduced for S- compared with *1/*1, but increased for R-warfarin. Bootstrap statistics for CL and V for each enantiomer are shown in Table 1.
Table 1 Warfarin pharmacokinetic parameters
|
Parameters |
Mean |
2.5% |
97.5% |
RSE (%) |
|
CLS L/h |
0.234 |
0.197 |
0.272 |
11 |
|
VS L |
25.40 |
22.40 |
28.41 |
6 |
|
CLR L/h |
0.141 |
0.120 |
0.155 |
12 |
|
VR L |
16.99 |
15.04 |
18.90 |
6 |
|
FCYP2C9 *1/*3 CLS |
0.818 |
0.652 |
0.975 |
11 |
|
FCYP2C9 *1/*3 CLR |
1.220 |
1.025 |
1.401 |
8 |
|
RUVS prop |
0.263 |
0.247 |
0.277 |
3 |
|
RUVS add mg/L |
0.005 |
0.002 |
0.008 |
27 |
|
RUVR prop |
0.230 |
0.217 |
0.241 |
3 |
|
RUVR add mcg/L |
0.000 |
0.000 |
0.000 |
0 |
A sigmoid Emax PD model inhibiting PCA synthesis best predicted INR as a function of S-warfarin concentration. R-warfarin effects were small and best described by competitive antagonism of S-warfarin. VKORC1 AA and CYP4F2 CC or CT genotype had lower C50 for S-warfarin. Bootstrap statistics for the potency of S-warfarin (C50S) and R-warfarin (IC50R) and the turnover half-life of PCA (T2PCA) are shown in Table 2.
Table 2 Warfarin PKPD and turnover parameters
|
Parameters |
Mean |
2.5% |
97.5% |
RSE (%) |
|
C50S mg/L |
0.386 |
0.261 |
0.552 |
21 |
|
HILL |
2.53 |
2.08 |
3.04 |
10 |
|
T2PCA h |
12.2 |
11.0 |
13.6 |
46 |
|
IC50R mg/L |
21.8 |
0.92 |
198 |
257 |
|
FVKORC1 AA C50 |
0.719 |
0.605 |
0.806 |
7 |
|
FCYP4F2 CC C50 |
0.767 |
0.637 |
0.869 |
8 |
|
FCYP4F2 CT C50 |
0.761 |
0.649 |
0.881 |
8 |
|
RUV prop |
0.180 |
0.168 |
0.191 |
3 |
Conclusions: A theory based PKPD model described warfarin concentrations and clinical response. Expected genotype effects were confirmed. The role of body composition as a determinant of PK parameters was identified. R-warfarin behaves more like a competitive antagonist of S-warfarin than a less potent inhibitor of PCA synthesis.
References:
[1] Holford NH. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet. 1986; 11(6):483-504.
[2] Anderson BJ, Holford NHG. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009; 24(1):25-36.
