Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial
2016 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 55, no 9, 1079-1090 p.Article in journal (Refereed) Published
Introduction: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.
Methods: Model development was performed using NONMEMA (R) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance.
Results: A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance.
Conclusion: Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (aecurrency sign60 kg), moderate renal impairment (CLCR aecurrency sign50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.
Place, publisher, year, edition, pages
2016. Vol. 55, no 9, 1079-1090 p.
IdentifiersURN: urn:nbn:se:uu:diva-305543DOI: 10.1007/s40262-016-0378-3ISI: 000382154200005PubMedID: 26951208OAI: oai:DiVA.org:uu-305543DiVA: diva2:1038980