Population Pharmacokinetic Models for Direct Oral Anticoagulants: A Systematic Review and Clinical Appraisal Using Exposure Simulation

Abstract

Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular attention. Population pharmacokinetic (PopPK) analyses can help in identifying such factors while providing predictive models. The main aim of the present study was to identify all the PopPK models to date for the four most frequently used DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban). The secondary aim was to use these models to simulate different DOAC plasma concentration–time profiles in relevant clinical scenarios. The results of our model‐based simulations confirm the clinical relevance of the known major factors influencing DOAC exposure and support the current approved dose adaptation, at least for atrial fibrillation. They also highlight how the accumulation of covariates, not currently considered for dose adaptation due to their seemingly minor influence on DOAC exposure, lead to supratherapeutic blood concentrations and could thus enhance the risk of major bleeding. The present results therefore question DOAC dose adaptation in the presence of these covariates, such as drug–drug interaction or genotypes, alongside the known existing covariates. As the overall effect of accumulation of several covariates could be difficult to apprehend for the clinicians, PopPK modeling could represent an interesting approach for informed precision dosing and to improve personalized prescription of DOACs.

Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban

“…The population approach is widely used to identify the pathophysiological factors that cause changes in the dose–exposure–response relationship and, accordingly, if dose adjustment is required. Terrier et al [ 14 ] reviewed the effect of covariates on exposure to rivaroxaban [ 14 ], but they did not assess the difference in PK/PD among various ethnicities. Moreover, several population PK and PK/PD studies in Asians were reported to identify significant covariates based on CL in recent years.…”

Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics

“…Of all the patientspecific factors known to influence DOAC concentrations, clearance, and efficacy and safety, kidney function demonstrates the most impact for the individual patient and the population of DOAC users. 67,68…”

“…This analysis demonstrated a lower efficacy for dabigatran and warfarin in patients with kidney impairment and a lower safety for all OACs. Of all the patient‐specific factors known to influence DOAC concentrations, clearance, and efficacy and safety, kidney function demonstrates the most impact for the individual patient and the population of DOAC users 67,68 …”

Population pharmacokinetics of apixaban in a real‐life hospitalized population from the OptimAT study

“…A dose‐modification strategy based on advanced age, low body weight, and reduced renal function was designed to minimize the potential for higher exposure in populations at inherently higher bleeding risk 8,9 . Although the results of clinical studies have indicated that each factor individually has limited effect on apixaban exposure, the combinations of two or more intrinsic factors may increase apixaban exposure to a much greater extent 10–13 . In addition, when apixaban is used in real‐world conditions and in populations outside the rigorous setting of clinical trials, a larger interpatient variability in plasma concentrations is expected with growing evidence correlating higher apixaban exposures and hemorrhages 14–18 .…”