RESUMEN
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.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Rivaroxabán/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Tiempo de Protrombina , Rivaroxabán/farmacologíaRESUMEN
BACKGROUND: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed. METHODS: We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration-time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5-18 years who had completed treatment for VTE. RESULTS: PK data from 59 children were obtained. The observed plasma concentration-time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions. CONCLUSIONS: These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5-18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.
RESUMEN
The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.