Pharmacokinetics and Dosing Regimens of Direct Oral Anticoagulants in Morbidly Obese Patients: An Updated Literature Review

Abstract

Data on the impact of morbid obesity (body mass index [BMI] ≥ 40 kg/m2) on the pharmacokinetics (PK), pharmacodynamics (PD) of direct oral anticoagulants (DOACs) are relatively limited, making it difficult to design optimal dosing regimens in morbidly obese patients. To review literature on PK/PD profile, efficacy, and safety of DOACs in venous thromboembolism (VTE) and nonvalvular atrial fibrillation (AF) patients with morbid obesity and make recommendations regarding optimal dosing regimens in these patient populations. A detailed literature search was conducted (from inception to June 22, 2022) for relevant articles involving PK/PD and clinical data on DOACs use in morbidly obese patients with VTE or AF, or healthy volunteers. A total of 28 studies were identified. DOAC-specific PK variations and clinical outcomes have been observed. Obesity may have a modest effect on PK/PD of dabigatran, apixaban, or rivaroxaban. Dabigatran was effective in AF patients with morbid obesity but might increase the risk of gastrointestinal bleeding. Standard dosing of apixaban or rivaroxaban is effective and safe for VTE and AF patients with morbid obesity. Trough edoxaban concentration and anti-Xa activity were similar in different BMI groups (18.5 to >40 kg/m2), and standard dosing of edoxaban may be effective and safe for AF patients. Current evidence suggests dabigatran should be used with caution in patients with AF as it might increase the risk of gastrointestinal bleeding; Standard dosing of apixaban or rivaroxaban can be used in VTE or AF patients; Standard dosing of edoxaban may be considered in AF patients.

Prediction of early neurological deterioration in acute ischemic stroke patients treated with intravenous thrombolysis

“…38,39 (2) Obese patients may be prone to have more complications such as venous thromboembolism. 40 (3) The clot-dissolving effect of alteplase may be hindered by PAI-1 which seems to be overexpressed in adipose tissue. 41 (4) The insufficient dose of thrombolysis drugs caused by overweight leads to a low recanalization rate after IVT.…”

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development

“…Importantly, recent popPK/PD analyses with a focus on individuals who are obese have been published for anticoagulants, 34,35 antimicrobial/antifungal drugs, [36][37][38][39][40][41][42][43][44][45][46] and analgesic/anesthetic drugs, [47][48][49] for example. These analyses can play an important role in how physicians approach treatment decisions.…”

Safety and efficacy of direct oral anticoagulants in comparison to warfarin in obese patients with atrial fibrillation: A systematic review and meta‐analysis

“…Obesity affects the pharmacokinetics of drugs by altering their volume of distribution (V d ), peak concentration (C max ), and drug exposure (area under curve, AUC), as well as drug clearance 11 . Thus, obesity also affected the pharmacokinetics and pharmacodynamics of DOACs among obese patients 12 . Due to concern about subanticoagulation with the use of fixed‐dose regimen, International Society on Thrombosis and Hemostasis (ISTH) (2016) recommended standard DOAC dosing for patients with a BMI ≤ 40 kg/m 2 and weight ≤ 120 kg for prevention of ischemic stroke and systemic arterial embolism in nonvalvular AF while cautioning against DOAC use in patients with a BMI > 40 kg/m 2 or weight > 120 kg due to limited data and potential pharmacokinetics or pharmacodynamic concerns.…”

“…They highlighted that the standard doses of apixaban, rivaroxaban, and edoxaban are effective and safe in morbidly obese patients with AF. At the same time, the body weight is inversely affected by the peak concentration of dabigatran, with a significantly increased risk of gastrointestinal bleeding 12 . There are now a growing number of studies studying the effectiveness and safety of the DOAC among obese or morbidly obese patients with AF, showing that they have better outcomes compared with those with normal BMI, and it's being depicted as an “obesity paradox.” 14 …”

“…At the same time, the body weight is inversely affected by the peak concentration of dabigatran, with a significantly increased risk of gastrointestinal bleeding. 12 There are now a growing number of studies studying the effectiveness and safety of the DOAC among obese or morbidly obese patients with AF, showing that they have better outcomes compared with those with normal BMI, and it's being depicted as an "obesity paradox." 14 Earlier meta-analyses on the use of DOAC compared with warfarin in morbidly obese patients with AF showed mixed results.…”