RESUMEN
Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabigatran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Bencimidazoles/farmacocinética , Piridinas/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Química Farmacéutica/métodos , Simulación por Computador , Dabigatrán , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Ortopedia/métodos , Tiempo de Tromboplastina Parcial , Trombina/antagonistas & inhibidores , Factores de TiempoRESUMEN
BACKGROUND: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. OBJECTIVES: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. PATIENTS AND METHODS: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. RESULTS: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. CONCLUSIONS: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.