Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling.

Abstract

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure–response analyses, the aim of the present study was to investigate the use of PT‐adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT‐adjustment approaches were established using time‐matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT‐adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate‐only exposure estimates.