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Population Pharmacokinetics of Intra-articular and Intravenous Administration of Tranexamic Acid in Patients Undergoing Total Knee Replacement

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Abstract

Background

Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported.

Aims

The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment.

Methods

Patients who underwent primary unilateral total knee replacement (TKR) received 1 g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2 g (two doses of 1 g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance.

Results

Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7 years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported.

Conclusions

This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8 h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA.

Trial Registration

Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.

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Acknowledgements

The authors thank the patients who participated in this study and the Research Institute of Hospital de la Santa Creu i Sant Pau—UICEC Sant Pau, which monitored the study. They also thank Jane Marshall for editing the manuscript. Aránzazu Gonzalez-Osuna is a PhD candidate in Surgery and Morphologic Sciences at the Autonomous University of Barcelona (Spain). Dr Mª José Martinez Zapata is funded by a Miguel Servet research contract from the Instituto de Salud Carlos III (CPII20/00023). The members of FARMATX Study Group: Dr. Adriá Font Gual, Dr. Aránzazu González Osuna, Dr. Claudia Lamas, Dr. Eduard Ramirez, Mrs Esther Cánovas Martínez, Mr Francesc Pla-Junca, Dr. José Antonio Fernández Nuñez, Dr. José Carlos González Rodriguez, Ms Luisa Fernanda Rojas, Dr. Marcos Jordán Sales, Dr. Mireia Rodríguez Prieto, Dr. Mª José Martínez-Zapata, Dr. Marta Valle, Dr. Sebastián Videla, Dr. Victoria Baños Lapuente, Dr. Xavier Aguilera Roig.

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Authors and Affiliations

  1. Orthopaedic Surgery and Traumatology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    Aránzazu González Osuna, Claudia Lamas & Xavier Aguilera Roig

  2. Department of Pharmacology, Therapeutics and Toxicology, Universidad Autónoma de Barcelona, Bellaterra, Barcelona, Spain

    Luisa Fernanda Rojas, Francesc Pla-Junca & Marta Valle

  3. Clinical Research Support Unit, Clinical Pharmacology Department, Bellvitge University Hospital/Bellvitge Biomedical Research Institute (IDIBELL), Carrer de la Feixa Llarga, s/n, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Sebastián Videla

  4. Department of Pathology and Experimental Therapeutics, Faculty of Medicine, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

    Sebastián Videla

  5. Iberoamerican Cochrane Centre-Public Health and Clinical Epidemiology, IIBSant Pau, CIBERESP, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Mª Claret, 165, 08025, Barcelona, Spain

    Mª José Martínez-Zapata

  6. Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

    Claudia Lamas & Xavier Aguilera Roig

Authors
  1. Aránzazu González Osuna
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Consortia

FARMATX study group

  • Adriá Font Gual
  • , Aránzazu González Osuna
  • , Claudia Lamas
  • , Eduard Ramirez
  • , Esther Cánovas Martínez
  • , Francesc Pla-Junca
  • , José Antonio Fernández Nuñez
  • , José Carlos González Rodriguez
  • , Luisa Fernanda Rojas
  • , Marcos Jordán Sales
  • , Mireia Rodríguez Prieto
  • , Mª José Martínez-Zapata
  • , Marta Valle
  • , Sebastián Videla
  • , Victoria Baños Lapuente
  •  & Xavier Aguilera Roig

Corresponding authors

Correspondence to Sebastián Videla or Mª José Martínez-Zapata.

Ethics declarations

Conflict of interest

Aránzazu González Osuna, Luisa Fernanda Rojas, Claudia Lamas, Xavier Aguilera Roig, Francesc Pla-Junca, Sebastián Videla, Mª José Martínez-Zapata, and Marta Valle declare they have no conflicts of interest.

Funding

This study was supported by internal sources from the Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Ethics approval

The clinical trial was approved by the Investigational Review Board of Hospital de Santa Creu i Sant Pau, Barcelona, Spain. This study was conducted in accordance with the principles of the Declaration of Helsinki. A high level of confidentiality, in terms of protection of personal data as required by Spanish Law (LOPD 3/2018), was also ensured.

Consent to participate

Patients who agreed to participate signed a written informed consent form.

Consent for publication

Not applicable.

Availability of data and material

Research data are not shared.

Code availability

Not applicable. The clinical trial protocol was registered in the Spanish Registry of Clinical Studies database (https://reec.aemps.es; number 2017-004159-22).

Author contributions

AGO, MV, LFR, XAR, FP-J, MJM-Z, and SV were involved in the conception and design of the study and/or the analysis and interpretation of the data. AGO and XAR were involved in the acquisition of data. MV, LFR and FP-J performed the pharmacokinetics analysis. AGO, MV, LFR, XAR, MJM-Z, and SV wrote the manuscript. All authors revised the article critically for important intellectual content and gave approval for the final version to be published.

Additional information

The members of FARMATX Study Group are listed in acknowledgements.

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González Osuna, A., Rojas, L.F., Lamas, C. et al. Population Pharmacokinetics of Intra-articular and Intravenous Administration of Tranexamic Acid in Patients Undergoing Total Knee Replacement. Clin Pharmacokinet 61, 83–95 (2022). https://doi.org/10.1007/s40262-021-01043-9

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