An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults

Kenneth Duchin, Anil Duggal, George J Atiee, Motonori Kidokoro, Tadanobu Takatani, Nicole Lazarus Shipitofsky, Ling He, George Zhang, Tarundeep Kakkar, Kenneth Duchin, Anil Duggal, George J Atiee, Motonori Kidokoro, Tadanobu Takatani, Nicole Lazarus Shipitofsky, Ling He, George Zhang, Tarundeep Kakkar

Abstract

Background: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism.

Objectives: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree.

Methods: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences.

Results: Total edoxaban exposure was similar between the intact and crushed tablet regimens (mean area under the plasma concentration-time curve from time zero to infinity: whole tablet, 2132 ng·h/mL; nasogastric tube, 2021 ng·h/mL; apple puree, 2076 ng·h/mL). Mean maximum plasma concentration, area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, terminal half-life, and apparent total body clearance values were also similar. Time to maximum plasma concentration was significantly shorter for the nasogastric tube suspension and apple puree vs. the whole tablet [Hodges-Lehmann estimate of median difference (90% confidence interval): -0.75 (-1.25, -0.28); p = 0.0003 and -0.62 (-0.99, -0.26); p = 0.0024, respectively]. The maximum plasma concentation, area under the plasma concentration-time curve from time zero to infinity, and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80-125% bioequivalence criterion. The safety and tolerability of edoxaban did not differ between treatment regimens.

Conclusion: The results support the use of edoxaban tablets crushed and administered either via a nasogastric tube or orally mixed in apple puree in patients who are unable to swallow solid oral dose formulations.

Conflict of interest statement

Funding

The study was funded by Daiichi Sankyo, Inc. (Parsippany, NJ, USA).

Conflict of interest

Anil Duggal, Motonori Kidokoro, Tadanobu Takatani, Nicole Shipitofsky, Ling He, George Zhang, and Tarundeep Kakkar are employees of Daiichi Sankyo, Inc.

Figures

Fig. 1
Fig. 1
Plasma edoxaban concentration–time profiles following administration of a single, oral 60-mg edoxaban tablet with water (Treatment A), a 60-mg edoxaban tablet crushed and given as a suspension via a nasogastric tube (Treatment B), or a 60-mg edoxaban tablet crushed and given orally mixed with apple puree (Treatment C). a Mean plasma edoxaban concentration–time profiles. b Semi-logarithmic mean plasma edoxaban concentration–time profiles. Inset Concentration–time profiles for the first 10 h only. Error bars represent the standard deviation
Fig. 2
Fig. 2
Plasma M-4 concentration–time profiles following administration of a single, oral 60-mg edoxaban tablet with water (Treatment A), a 60-mg edoxaban tablet crushed and given as a suspension via a nasogastric tube (Treatment B), or a 60-mg edoxaban tablet crushed and given orally mixed with apple puree (Treatment C). a Mean plasma M-4 concentration–time profiles. b Semi-logarithmic mean plasma M-4 concentration–time profiles. Inset Concentration–time profiles for the first 10 h only. Error bars represent the standard deviation

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