Bioequivalence Study of 2 Formulations of Rivaroxaban, a Narrow‐Therapeutic‐Index Drug, in Healthy Chinese Subjects Under Fasting and Fed Conditions

Ding, Sijia; Wang, Lu; Xie, Ling; Zhou, Siyu; Chen, Juan; Zhao, Yuqing; Deng, Wenjie; Liu, Yun; Zhang, Hongwen; Shao, Feng

doi:10.1002/cpdd.742

Cited by 11 publications

(15 citation statements)

References 13 publications

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“…Метод был селективен, нижний предел количественного определения (НПКО) ривароксабана составил 0,5 нг/мл. Согласно данным литературы, такой НПКО обеспечивает определение концентрации на уровне менее 5% от C max [13]. Линейный диапазон метода 0,5-400 нг/мл.…”

Section: аналитический метод и хроматографическая системаunclassified

“…Исследование состояло из периода скрининга (до 10 сут), двух периодов забора образцов крови после приема препаратов (48 ч) и периода «отмывки» (7 сут), завершения исследования. Период наблюдения уровня концентрации ривароксабана в крови после приема препарата был выбран на основании данных литературы 3 [13], где указано, что 48 ч достаточно для достижения площади под фармакокинетической кривой (кривой «концентрация-время», AUC) более 80% от AUC 0-∞ .…”

Section: Introductionunclassified

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Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Gildeeva

Chaplenko

Yurkov

et al. 2022

Bezopasnost' i risk farmakoterapii

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Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics.The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions.Materials and methods: the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto®, 10 mg filmcoated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once; blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).Results: no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto®, respectively: Cmax of 134.6 ± 58.0 ng/mL and 139.9 ± 49.3 ng/mL, AUC0–48 of 949.7 ± 354.5 ng×h/mL and 967.6 ± 319.9 ng×h/mL, AUC 0–∞ of 986.9 ± 379.7 ng×h/mL and 1003.6 ± 320.4 ng×h/mL, T1/2 of 8.2 ± 3.2 h and 7.8 ± 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0–48, and AUC0–∞ geometric means were 88.04–108.67%, 89.42–104.92% and 89.44–104.81%, respectively.Conclusions: the test product Rivaroxaban and the reference product Xarelto® were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products.

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Section: аналитический метод и хроматографическая системаunclassified

Section: Introductionunclassified

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Gildeeva

Chaplenko

Yurkov

et al. 2022

Bezopasnost' i risk farmakoterapii

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“…Different studies have been demonstrating the effect of feeding on the pharmacokinetics of rivaroxaban (Kubitza et al, 2006;Zhang et al, 2017;Ding et al, 2019). At doses up to 10 mg, rivaroxaban exhibits linear pharmacokinetics, and its absorption remains unchanged, regardless of the presence of food (Kubitza et al, 2005;Kubitza et al, 2006;Zhang et al, 2017).…”

Section: Pharmacokinetic Parameters and Bioequivalencementioning

confidence: 99%

“…Overall, rivaroxaban has been demonstrating safety and tolerability when administered to healthy subjects (Kubitza et al, 2005;Kubitza et al, 2008;Zhao et al, 2009;Ding et al, 2019). In the PK/PD study published by Kubitza and colleagues (2005), which included 103 healthy men receiving single doses of 1.25 mg to 80 mg of rivaroxaban, the incidence of AEs was similar between subjects receiving placebo and those receiving rivaroxaban.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Relative bioavailability/bioequivalence between two oral formulations of rivaroxaban (20 mg) in healthy brazilian subjects, under fasting and fed conditions

Loschi¹,

Rezende²,

Santos³

et al. 2022

Braz. J. Hea. Rev.

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O estudo teve como objetivo avaliar a bioequivalência entre dois comprimidos revestidos de rivaroxabana em participantes brasileiros saudáveis após administração em dose única em condições de jejum e alimentação. Dois estudos foram conduzidos com um desenho aberto, randomizado, cruzado com duas sequências, quatro períodos e washout de sete dias entre os períodos. Foram realizadas coletas seriadas de sangue para quantificar a concentração plasmática de rivaroxabana e realizar a análise farmacocinética. A bioequivalência é confirmada se os intervalos de confiança de 90% (IC de 90%) para a razão entre as médias geométricas das duas formulações estiverem dentro dos limites de bioequivalência de 80-125% para a área sob a curva do tempo 0 à última concentração mensurável (AUC0-t) e concentração máxima (Cmax). Além disso, o limite superior do IC de 90% para a razão da variabilidade intra-sujeito (σWT/σWR) entre ambas as formulações deve ser ≤ 2,5. Os pontos estimados e o IC de 90% para AUC0-t (102,4; 97,3-107,9), Cmax (97,5; 91,6-103,7), σWT/σWR para AUC0-t (0,70; 0,51-0,95) e σWT/σWR para Cmax (0,94; 0,69-1,28) demonstraram que ambas as formulações foram bioequivalentes no estudo jejum. Resultados semelhantes foram obtidos para AUC0-t (99,5; 96,1-103,1), Cmax (98,9; 95,1-102,9), σWT/σWR para AUC0-t (0,94; 0,70-1,25) e σWT/σWR para Cmax (0,97; 0,73-1,30) no estudo alimentado. Assim, as formulações têm biodisponibilidade sistêmica equivalente sob condições de jejum e alimentação, e um desempenho clínico semelhante pode ser esperado.

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“…11 In a previous study, the subject was administered 10 mg of rivaroxaban, which indicated that the PK parameters were similar in the fasted and fed conditions. 5,12 However, at high doses, food showed an obvious influence on the PK of rivaroxaban. In this study, with the highfat breakfast before dosing, the C max increased by 73%, the AUC 0-t increased by 50%, the AUC 0-∞ increased by 33%, and the terminal half-life was shortened, which is similar to the results of previous studies.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Bioequivalence and Food Effect Assessment of 2 Rivaroxaban Formulations in Healthy Chinese Volunteers: An Open, Randomized, Single‐Dose, and 4‐Period Crossover Study

Tao

Jiang

Shi

et al. 2021

Clinical Pharm in Drug Dev

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Rivaroxaban is a direct factor Xa inhibitor used for the management of thromboembolic disorders. The aim of this study was to evaluate the safety, pharmacokinetic profile, and bioequivalence of a generic and a branded rivaroxaban formulation (Xarelto) under fasted and fed conditions in healthy Chinese volunteers. An open-label, randomized, singledose, 4-period complete, and replicate crossover study in healthy Chinese volunteers was performed. A single oral dose of 20 mg of 2 rivaroxaban formulations was administered to 72 healthy volunteers, with 36 in the fasted group and 36 consuming a high-fat diet. The evaluated pharmacokinetic parameters, including maximum rivaroxaban concentration, the area under the concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity, were assessed for BE. The plasma concentrations of rivaroxaban were measured by a validated liquid chromatography-tandem mass spectrometry method. The geometric mean ratios with 90% confidence intervals of the maximum rivaroxaban concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity were all within the range of 80% to 125% under fasted and fed conditions. The within-subject variability of the test and reference products was compared, and the upper limit of the 90% confidence intervals for the test-to-reference ratio of the within-subject variability was <2.5, which indicated that the rivaroxaban test and the rivaroxaban reference formulation were bioequivalent. No serious adverse events were reported during either fasted or fed conditions of the study.

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Bioequivalence Study of 2 Formulations of Rivaroxaban, a Narrow‐Therapeutic‐Index Drug, in Healthy Chinese Subjects Under Fasting and Fed Conditions

Cited by 11 publications

References 13 publications

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Relative bioavailability/bioequivalence between two oral formulations of rivaroxaban (20 mg) in healthy brazilian subjects, under fasting and fed conditions

Bioequivalence and Food Effect Assessment of 2 Rivaroxaban Formulations in Healthy Chinese Volunteers: An Open, Randomized, Single‐Dose, and 4‐Period Crossover Study

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