Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats

Q: What are the key findings of this study?

Ticagrelor pre-treatment significantly increased rivaroxaban AUC(0–t) from 1060.97 to 3483.03 μg·h/L and Cmax from 221.34 to 691.18 ng/mL (both p<0.05) in rats.

Q: What is the clinical evidence from this study?

Population: Pharmacokinetic drug-drug interaction between ticagrelor and rivaroxaban in Sprague-Dawley rats (n=10). Intervention: Ticagrelor pre-treatment prior to single-dose rivaroxaban vs. Equal amounts of vehicle (CMC-Na solution) for 14 days, followed by rivaroxaban 10 mg/kg single oral dose. Primary outcome: Rivaroxaban area under the plasma concentration-time curve from 0 to t (AUC0-t, μg·h/L) (p=<0.05).

Q: What does this research mean for the field?

Pre-treatment with ticagrelor significantly increases systemic exposure and reduces metabolic clearance of rivaroxaban in rats. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To investigate the in vivo and in vitro effects of ticagrelor on the pharmacokinetic profile and metabolic clearance of rivaroxaban in rats.

Jia Wen Chong; Hao Chen; Da‐Peng Dai; Shuanghu Wang; Quan Zhou; Junpeng Liu; You Lü; Hualan Wu; Minghui Du; Feifei Chen; Hui Jiang; Yunfang Zhou; Jiefu Yang

doi:10.1080/13880209.2020.1785510

January 1, 2020Pharmaceutical BiologyOpen Access

Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats

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Key result

Ticagrelor pre-treatment increases rivaroxaban exposure ~3.3-fold in rats.

P<0.05
n=10

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Why the study?

Rivaroxaban and ticagrelor are commonly used for atrial fibrillation and acute coronary syndrome, but potential drug-drug interactions between them remain unknown.

Does ticagrelor pre-treatment alter the pharmacokinetic exposure and metabolic clearance of rivaroxaban in rats?

Key Points

To investigate the in vivo and in vitro effects of ticagrelor on the pharmacokinetic profile and metabolic clearance of rivaroxaban in rats.
Ten Sprague-Dawley rats were randomly assigned to a ticagrelor pre-treated group (10 mg/kg/day for 14 days, n=5) or a control group (n=5) before receiving a single oral dose of rivaroxaban (10 mg/kg).
Plasma rivaroxaban concentrations were quantified using a newly developed UPLC-MS/MS method.
Sprague-Dawley rat liver microsomes were incubated with rivaroxaban and varying concentrations of ticagrelor (1 to 100 μM) to evaluate in vitro metabolic inhibition.
Pre-treatment with ticagrelor significantly increased rivaroxaban Cmax from 221.34 ± 53.33 to 691.18 ± 238.31 ng/mL and AUC(0–t) from 1060.97 ± 291.21 to 3483.03 ± 753.83 μg·h/L (both p < 0.05).
Rivaroxaban MRT(0–∞) prolonged from 4.41 ± 0.79 to 5.97 ± 1.11 h, while intrinsic clearance dropped from 9.93 ± 2.55 to 2.89 ± 0.63 L/h/kg (both p < 0.05).
In rat liver microsomes, ticagrelor inhibited rivaroxaban metabolism in a dose-dependent manner with an IC50 of 14.04 μmol/L.

Structured PICO

Does ticagrelor pre-treatment alter the pharmacokinetic exposure and metabolic clearance of rivaroxaban in rats?

P

Population

10 male Sprague-Dawley rats (220 ± 20 g) randomized to 14 days of ticagrelor pre-treatment or vehicle control followed by a single oral dose of rivaroxaban with 24-hour pharmacokinetic monitoring.

I

Intervention

Ticagrelor 10 mg/kg/day via oral gavage (dissolved in CMC-Na solution) for 14 days prior to a single oral gavage dose of rivaroxaban 10 mg/kg; in vitro incubation with ticagrelor (1 to 100 μM).

C

Comparator

Equal amounts of vehicle (CMC-Na solution) via oral gavage for 14 days prior to a single oral gavage dose of rivaroxaban 10 mg/kg.

O

Outcome

Pharmacokinetic parameters of rivaroxaban over 24 hours, primarily AUC(0–t) and Cmax determined by UPLC-MS/MS.surrogate

Main Result

Absolute Event Rate: 3483.03% vs 1060.97%

p-value: p=<0.05

Limitations

Pharmacokinetic effects of ticagrelor on rivaroxaban found in rats may not necessarily exist in humans.
Explorative and preliminary study lacking detailed information on the specific inhibition type and precise molecular mechanisms of the drug-drug interaction.
Pharmacokinetic effects found in rats may not necessarily apply to humans
Explorative and preliminary study with no further information on the exact inhibition type and precise mechanisms of ticagrelor on rivaroxaban metabolism

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Implication

Pre-treatment with ticagrelor increases systemic exposure (AUC by 3.3-fold and Cmax by 3.1-fold) and reduces metabolic clearance of rivaroxaban in rats, suggesting a potential pharmacokinetic drug–drug interaction that warrants human investigation.

Abstract

Context Rivaroxaban and ticagrelor are two common drugs for the treatment of atrial fibrillation and acute coronary syndrome. However, the drug–drug interaction between them is still unknown.Objective To investigate the effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats both in vivo and in vitro.Materials and methods A sensitive and reliable UPLC-MS/MS method was developed for the determination of rivaroxaban in rat plasma. Ten Sprague-Dawley rats were randomly divided into ticagrelor pre-treated group (10 mg/kg/day for 14 days) and control group. The pharmacokinetics of orally administered rivaroxaban (10 mg/kg, single dose) with or without ticagrelor pre-treatment was investigated with developed UPLC-MS/MS method. Additionally, Sprague-Dawley rat liver microsomes were also used to investigate the drug–drug interaction between these two drugs in vitro.Results The Cmax (221.34 ± 53.33 vs. 691.18 ± 238.31 ng/mL) and the AUC(0–t) (1060.97 ± 291.21 vs. 3483.03 ± 753.83 μg·h/L) of rivaroxaban increased significantly (p < 0.05) with ticagrelor pre-treatment. The MRT(0–∞) of rivaroxaban increased from 4.41 ± 0.79 to 5.97 ± 1.11 h, while the intrinsic clearance decreased from 9.93 ± 2.55 to 2.89 ± 0.63 L/h/kg (both p < 0.05) after pre-treated with ticagrelor. Enzyme kinetic study indicated that ticagrelor decreased rivaroxaban metabolic clearance with the IC50 value of 14.04 μmol/L.Conclusions Our in vivo and in vitro results demonstrated that there is a drug–drug interaction between ticagrelor and rivaroxaban in rats. Further studies need to be carried out to verify whether similar interactions truly apply in humans and whether these interactions have clinical significance.

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Cite This Study

Chong et al. (2020) studied Pharmacokinetic drug-drug interaction between ticagrelor and rivaroxaban in Sprague-Dawley rats (n=10). Ticagrelor pre-treatment prior to single-dose rivaroxaban vs. Equal amounts of vehicle (CMC-Na solution) for 14 days, followed by rivaroxaban 10 mg/kg single oral dose was evaluated on Rivaroxaban area under the plasma concentration-time curve from 0 to t (AUC0-t, μg·h/L) (p=<0.05). Ticagrelor pre-treatment significantly increased rivaroxaban AUC(0–t) from 1060.97 to 3483.03 μg·h/L and Cmax from 221.34 to 691.18 ng/mL (both p<0.05) in rats.

synapsesocial.com/papers/6a735c64f0b147c119b872ee https://doi.org/10.1080/13880209.2020.1785510

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Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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