In Vitro Assessment of Pharmacokinetic Drug-Drug Interactions of Direct Oral Anticoagulants: Type 5-Phosphodiesterase Inhibitors Are Inhibitors of Rivaroxaban and Apixaban Efflux by P-Glycoprotein

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

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In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition

European Journal of Drug Metabolism and Pharmacokinetics ◽

10.1007/s13318-017-0434-x ◽

2017 ◽

Vol 43 (2) ◽

pp. 183-191 ◽

Cited By ~ 21

Author(s):

Sophie Hodin ◽

Thierry Basset ◽

Elodie Jacqueroux ◽

Olivier Delezay ◽

Anthony Clotagatide ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Cancer Resistance ◽

P Glycoprotein ◽

Resistance Protein ◽

In Vitro Comparison

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Clinical Management of Pharmacokinetic Drug Interactions with Direct Oral Anticoagulants (DOACs)

Drugs ◽

10.1007/s40265-019-01183-0 ◽

2019 ◽

Vol 79 (15) ◽

pp. 1625-1634 ◽

Cited By ~ 6

Author(s):

Megan C. Herink ◽

Yan F. Zhuo ◽

Craig D. Williams ◽

Thomas G. DeLoughery

Keyword(s):

Drug Interactions ◽

Clinical Management ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Pharmacokinetic Drug

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Drug–Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620936325 ◽

2020 ◽

Vol 26 ◽

pp. 107602962093632 ◽

Cited By ~ 1

Author(s):

Érique José F. Peixoto de Miranda ◽

Thamy Takahashi ◽

Felipe Iwamoto ◽

Suzete Yamashiro ◽

Eliana Samano ◽

...

Keyword(s):

Tyrosine Kinase ◽

Supportive Care ◽

Drug Interactions ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

P Glycoprotein ◽

Clinically Significant ◽

Potentially Clinically Significant

Data on drug–drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug–drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug–drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug–drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

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Evaluation of Drug Interactions with P-Glycoprotein in Drug Discovery: In Vitro Assessment of the Potential for Drug-Drug Interactions with P-Glycoprotein

Current Drug Metabolism ◽

10.2174/1389200023337559 ◽

2002 ◽

Vol 3 (3) ◽

pp. 257-273 ◽

Cited By ~ 81

Author(s):

Jerome Hochman ◽

Masayo Yamazaki ◽

Tomoyuki Ohe ◽

Jiunn Lin

Keyword(s):

Drug Discovery ◽

Drug Interactions ◽

P Glycoprotein ◽

In Vitro Assessment

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Pharmacokinetic Drug-drug Interaction of Antibiotics Used in Sepsis Care in China

Current Drug Metabolism ◽

10.2174/1389200221666200929115117 ◽

2020 ◽

Vol 21 ◽

Author(s):

Xuan Yu ◽

Zixuan Chu ◽

Jian Li ◽

Rongrong He ◽

Yaya Wang ◽

...

Keyword(s):

Drug Interaction ◽

Drug Interactions ◽

Penicillin G ◽

Literature Mining ◽

Human Pharmacokinetics ◽

P450 Enzyme ◽

Drug Drug Interaction ◽

Pharmacokinetic Drug ◽

Sepsis Care

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.

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Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation

European Heart Journal ◽

10.1093/ehjci/ehaa946.3776 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M.M Engelen ◽

C Van Laer ◽

M Jacquemin ◽

C Vandenbriele ◽

K Peerlinck ◽

...

Keyword(s):

Thrombin Generation ◽

Heart Valves ◽

Thrombus Formation ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factor ◽

Mechanical Heart Valves ◽

Contact Activation

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

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Drug-drug interactions with direct oral anticoagulants: practical recommendations for clinicians

The American Journal of Medicine ◽

10.1016/j.amjmed.2021.04.003 ◽

2021 ◽

Author(s):

Terrier Jean ◽

Gaspar Frédéric ◽

Fontana Pierre ◽

Daali Youssef ◽

Reny Jean-Luc ◽

...

Keyword(s):

Drug Interactions ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Practical Recommendations

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