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Pharmacokinetics of oral spironolactone in infants up to 2 years of age

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Abstract

Purpose

Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age.

Methods

The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed‐effects modelling software Monolix 2018R2.

Results

A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days–21 months; median weight 4.3 kg (2.2–12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period.

Conclusion

The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013–001189-40).

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Availability of data and materials

The manuscript contains 2 tables, 3 figures, 2 supplemental tables and 2 supplemental figures.

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Acknowledgements

We would like to thank Gedeon Ricther for the donation of spironolactone powder, Dr P. Tähepõld, Dr S. Virro, and personnel of the Department of Cardiothoracic Surgery and Pediatric and Paediatric Intensive Care Unit (PICU) of Tartu University Hospital for their help in recruiting patients.

Funding

This research program was funded under the ERANet PRIOMEDCHILD program (Proposal No 40–41800-98–022).

Author information

Author notes

  1. Jana Lass and Stephanie Leroux contributed equally to this work.

Authors and Affiliations

  1. Institute of Pharmacy, University of Tartu, Tartu, Estonia

    Jana Lass

  2. Pharmacy Department, Tartu University Hospital, Tartu, Estonia

    Jana Lass

  3. University Children’s Hospital Basel, University of Basel, Basel, Switzerland

    Stephanie Leroux, Marc Pfister & Johannes van den Anker

  4. Paediatric Department, Rennes University Hospital, Rennes, France

    Stephanie Leroux

  5. Haematology and Oncology Clinic of Tartu University Hospital, Tartu, Estonia

    Lenne-Triin Kõrgvee

  6. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

    Lenne-Triin Kõrgvee, Tuuli Metsvaht, Hiie Soeorg & Irja Lutsar

  7. Neonatal Unit, Children’s Clinic, Tartu University Hospital, Tartu, Estonia

    Heili Varendi

  8. Institute of Chemistry, University of Tartu, Tartu, Estonia

    Karin Kipper, Kalev Takkis & Rudolf Aro

  9. Analytical Services International, St George’s University of London, London, UK

    Karin Kipper

  10. Clinic of Anesthesiology and Intensive Care, Pediatric Intensive Care Unit, Tartu University Hospital, Tartu, Estonia

    Tuuli Metsvaht

  11. Oncology Department, North Estonian Medical Centre, Tallinn, Estonia

    Kersti Oselin

  12. Children’s National Hospital, Washington, DC, USA

    Johannes van den Anker

Authors
  1. Jana Lass
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  2. Stephanie Leroux
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  3. Lenne-Triin Kõrgvee
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Contributions

JL and SL wrote the manuscript. L-TK, HV, TM, KO, and IL participated in designing and conducting of the study. SL, JvdA, MP, and HS participated in the analysis of the study. KK, KT, and RA did the analysis of the samples. All authors reviewed the manuscript.

Corresponding author

Correspondence to Jana Lass.

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Ethical approval

The study was approved of the Research Ethics Committee of the University of Tartu (Approval No 249[M-12).

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Individuals have been given consent to participate in a study and consent having their data published in a journal article.

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The authors declare no competing interests.

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Lass, J., Leroux, S., Kõrgvee, LT. et al. Pharmacokinetics of oral spironolactone in infants up to 2 years of age. Eur J Clin Pharmacol 80, 239–248 (2024). https://doi.org/10.1007/s00228-023-03599-w

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