Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations

Abstract

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

External validation and updating of the infusion rate individualization of soybean oil–based intravenous lipid emulsion: A descriptive cohort study

“…Because the prediction performance is not dependent on infusion rates, we involved all patients, including MaxInfRate‐eligible and MaxInfRate‐ineligbile patients, in evaluating the TG kinetic model prediction performance. The prediction performance was checked using traditional prediction‐based and simulation‐based diagnostics 8 and by comparing a model‐predicted Kel value with the observed value, 9 using all the study patients. These evaluations are useful in identifying potential biases and/or inaccuracies of a kinetic model based on a nonlinear mixed‐effect model.…”