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

Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: body size; fat free mass; international normalized ratio; pharmacogenomics; turnover; warfarin.

© 2016 The British Pharmacological Society.

Figures

Figure 1

Minimal model Pred Corrected visual predictive checks of S‐ and R‐warfarin concentration time course over 12 weeks. Observed (with symbols) and predicted 5, 50 and 95 percentiles, with predicted 95% confidence intervals (shaded)

Figure 2

Minimal model Pred Corrected visual predictive checks of international normalized ratio time course over 28 days and 12 weeks. Observed (with symbols) and predicted 5, 50 and 95 percentiles, with predicted 95% confidence intervals (shaded)

Figure 3

Predicted time course of S‐ and R‐warfarin concentrations and international normalized ratio in a standard size patient (FFM 56.1 kg) with the most frequent genotypes CYP2C9 *1/*1, VKORC1 AA, CYP4F2 CC (upper plots), and least frequent genotypes CYP2C9 *1/*3, VKORC1 GG, CYP4F2 TT (lower plots). Maintenance dose rates (MDR) chosen to achieve target INR of about 2 (left plots). Loading dose (LD) chosen to approach steady state concentrations plus MDR (right plots)