Journal of Thrombosis and Haemostasis | 2021
Fixed dose rivaroxaban can be used in extremes of bodyweight: A population pharmacokinetic analysis ‐ Reply to Jacobs & Ryan comment
Abstract
We thank Jacobs and Ryan for their letter and interest in our work.1 The purpose of any population pharmacokinetic analysis is to identify the significant covariates that best describe the data. Our analysis suggests that renal function as estimated by the CockcroftGault method is the most significant covariate affecting the pharmacokinetics of rivaroxaban in our population, which represents a typical population attending anticoagulation clinics. In our analysis, both lean body weight and actual body weight were significant covariates during the model-building process. However, the influence of weight as a covariate was not as significant as when incorporated into the Cockcroft-Gault equation estimating renal function. Because body weight is already captured into this equation, it made no physiological sense to add it, in addition to renal function, onto the estimates of rivaroxaban clearance. We therefore concur with Jacobs and Ryan, weight does have an influence on rivaroxaban exposure; this has already been demonstrated both in earlier industry studies,2,3 as well as our own data and our simulations. However, the difference between the very obese and normally weighted patients are not significant enough to warrant a different dosing regimen for rivaroxaban. This is borne out from our clinical experience, where when we assay trough concentrations in the very obese, they are comparable to normally weighted patients, which is reassuring in our opinion. We are not the only group to describe this and there is now sufficient published evidence to warrant the use of rivaroxaban in patients up to 150 kg, without the need to measure drug concentrations.4-8 In our practice, we currently prescribe rivaroxaban beyond 150 kg, with measurement of trough concentrations, and as further clinical experience continues to be shared, this threshold will also increase in our view. In their letter, Jacobs and Ryan stated a desire to see a breakdown of the concentrations of rivaroxaban for patients > 120 kg. The data in the model developed were collected at routine clinic appointments; as such, plasma concentrations were not necessarily obtained at a peak or a trough. With such sparse data, the population pharmacokinetic modelling approach allows us to evaluate the population as a whole. Using this approach, population estimates of apparent clearance and apparent volume of distribution were the focus of this analysis. For interested readers, Figure 2 of the supplemental material does plot the time after dose versus the observed concentrations for patients > 120 kg as part of a visual predictive check, and is reassuring because it demonstrates that the final model is describing the data well in this subpopulation. Unlike Jacobs and Ryan, we believe it is not impossible to answer this important clinical question through clinical trials. Industry should ensure that their landmark clinical trial designs reflect more closely the heterogenous patients we are challenged to provide care for on a daily basis, not the narrow demographic population that are often are recruited in these studies. In fact, regulators should demand this from such trials. This would then allow modelling studies from these trials that would then be able to address these important questions in the early days after a drug is approved. Since the ISTH published their guidance on this issue in 2016, a lot of clinical experience has been published on the use of rivaroxaban in the very obese.4-9 In addition to the retrospective study cited by Jacobs and Ryan, there are prospective data to draw from as well as a number of other retrospective studies and large claims database studies in the setting of atrial fibrillation and venous thromboembolism (VTE). More recently, we shared reassuring findings from the FIRST registry of 97 patients > 120 kg or body mass index > 40 kg/ m2 who were treated for acute VTE with rivaroxaban; no cases of symptomatic recurrent VTE were reported from this UK-wide study.4 Similarly, Wysokinski and colleagues have reported prospective data from the Mayo Clinic in the United States. They found no difference in the rate of recurrent VTE in patients > 120 kg prescribed rivaroxaban or apixaban compared with traditional therapies with the exception of those with cancer-associated VTE.5 Their work is reassuring but does suggest that in the setting of cancer, further research is required and caution with the use of rivaroxaban and apixaban in this setting would be wise. We maintain that the ISTH should review its current guidance to ensure this subpopulation is not excluded from the benefits of direct oral anticoagulant therapy.