Premium
Model‐Based Assessment Using Conventional Bioequivalence Limits to Ensure Safety and Efficacy of Rivaroxaban in Patients Undergoing Hip or Knee Replacement
Author(s) -
GonzálezSales Mario,
Fang Lanyan,
Kim MyongJin,
Zhao Liang
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.930
Subject(s) - rivaroxaban , medicine , bioequivalence , area under the curve , clinical trial , pharmacokinetics , warfarin , atrial fibrillation
We evaluated whether the current bioequivalence limit is adequate to ensure safety and efficacy of rivaroxaban in patients under total hip arthroplasty and total knee arthroplasty based on its model informed benefit/risk profile. Clinical data from a total of 7145 patients from 3 phase 2 and 4 phase 3 clinical trials were included in the current model‐based exposure‐response analysis. The relationships between rivaroxaban exposure measurements (ie, minimum or trough, maximum, average concentration, and area under the concentration–time curve [AUC] at steady state) and clinical outcomes (ie, the probabilities of major bleeding [MB] and venous thromboembolism [VTE]) were modeled using NONMEM 7.3. Model evaluation was performed using predictive checks and nonparametric bootstrap. Simulations were conducted to assess the study objectives. A shallow relationship was observed between explored exposure measurements within the tested dose range and the probability of VTE following rivaroxaban treatment. Trough concentrations were found to be a statistically significant predictor of the probability of MB. This relationship was better described using a power function. Model validation confirmed model adequacy. Based on the simulations results, the relative risk of MB of a hypothetical test product (with 20% change in AUC) will not statistically differ from the brand name drug. Twenty percent AUC variations do not change the relative risk of MB and is unlikely to compromise efficacy of therapy. A generic drug of rivaroxaban passing the typical bioequivalence assessment is expected to have similar safety and efficacy as the brand name drug.