A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects

Barrett, Yu Chen; Wang, Jessie; Yan, Shijuan; Pursley, Janice; Wastall, Philip; Wright, Robin M.; LaCreta, Frank; Frost, Charles

doi:10.1160/th11-09-0634

Cited by 51 publications

(7 citation statements)

References 21 publications

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“…As observed in previous studies, the time course of anti-Xa activity closely tracked the apixaban plasma concentration–time profile, with a direct linear relationship between the two that exhibited no temporal lag 12,25. This is consistent with the parent compound being solely responsible for the observed anticoagulant activity, and is evident in the similarity between the anti-Xa activity peak-to-trough ratio (calculated based on observed maximum and minimum from the mean profile) of 2.9 and the apixaban concentration peak-to-trough ratio (2.9).…”

Section: Discussionsupporting

confidence: 81%

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

Chen¹,

Wang²,

Zhang³

et al. 2013

CPAA

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BackgroundThe pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study.Subjects and methodsEighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations.ResultsPK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported.ConclusionApixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race.

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Section: Discussionsupporting

confidence: 81%

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

Chen¹,

Wang²,

Zhang³

et al. 2013

CPAA

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“…Area under the concentration-time curve ratios (AUCR) and maximum (peak) concentration ratios (C max R) of apixaban with and without concomitantly taken drugs. Results of drug-drug interaction trials that have been conducted and published up to January 2020 are depicted[22,32,36,40,43,85,[98][99][100][101]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics.…”

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confidence: 99%

Drug–Drug Interactions with Direct Oral Anticoagulants

et al. 2020

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A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug-drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug-disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

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“…Accordingly, the 60-hour, intensively sampled pharmacokinetic monitoring period for apixaban and a 3-day washout period (approximately five elimination half-lives for apixaban) were considered appropriate in this study 14–16,27. The famotidine dose (40 mg) and time interval (administered 3 hours prior to apixaban) in combination with the dose of apixaban (10 mg) were considered to represent the largest potential for an interaction due to gastric acid suppression.…”

Section: Discussionmentioning

confidence: 99%

Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Upreti

Wang²,

Byon³

et al. 2013

CPAA

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BackgroundApixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects.MethodsThis two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated.ResultsFamotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated.ConclusionFamotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to underlying conditions (eg, achlorhydria), or by gastrointestinal pH-mediated effects of other histamine H2-receptor antagonists, antacids, or proton pump inhibitors. Given that famotidine is also an inhibitor of the human organic cation transporter (hOCT), these results indicate that apixaban pharmacokinetics are not influenced by hOCT uptake transporter inhibitors. Overall, these results support that apixaban can be administered without regard to coadministration of gastric acid modifiers.

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A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects

Cited by 51 publications

References 21 publications

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

Drug–Drug Interactions with Direct Oral Anticoagulants

Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

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