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Model-informed precision dosing of antimicrobial drugs in pediatrics: experiences from a pilot scale program

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Abstract

Antibiotics are among the most utilized drugs in pediatrics. Nonetheless, there is a lack in pharmacokinetics information for this population, and dosing criteria may vary between healthcare centers. Physiological variability associated with maturation in pediatrics makes it challenging to reach a consensus on adequate dosing, which is further accentuated in more vulnerable groups, such as critically ill or oncology patients. Model-informed precision dosing is a useful practice that allows dose optimization and attainment of antibiotic-specific pharmacokinetic/pharmacodynamic targets. The aim of this study was to evaluate the needs of model-informed precision dosing of antibiotics in a pediatrics unit, at a pilot scale. Pediatric patients under antibiotic treatment were monitored with either a pharmacokinetic/pharmacodynamic optimized sampling scheme or through opportunistic sampling. Clindamycin, fluconazole, linezolid, meropenem, metronidazole, piperacillin, and vancomycin plasma concentrations were quantified through a liquid chromatography coupled to mass spectrometry method. Pharmacokinetic parameters were estimated using a Bayesian approach to verify pharmacokinetic/pharmacodynamic target attainment. A total of 23 pediatric patients aged 2 to 16 years were included, and 43 dosing regimens were evaluated; 27 (63%) of them required adjustments as follows: 14 patients were underdosed, 4 were overdosed, and 9 patients needed infusion rate adjustments. Infusion rate adjustments were mostly recommended for piperacillin and meropenem; daily doses were augmented for vancomycin and metronidazole, meanwhile linezolid was adjusted for under- and overdosing. Clindamycin and fluconazole regimens were not adjusted at all.

  Conclusion: Results showcase a lack of antibiotic pharmacokinetic/pharmacodynamic target attainment (particularly for linezolid, vancomycin, meropenem, and piperacillin), and the need for model-informed precision dosing in pediatrics. This study provides pharmacokinetic evidence which can further improve antibiotic dosing practices.

What is Known:

• Model-informed precision dosing is performed in pediatrics to optimize the treatment of antimicrobial drugs such as vancomycin and aminoglycosides, while its usefulness is debated for other groups (beta-lactams, macrolides, etc.).

What is New:

• Vulnerable pediatric subpopulations, such as critically ill or oncology patients, can benefit the most from model-informed precision dosing of antibiotics.

• Model-informed precision dosing of linezolid, meropenem, piperacillin, and vancomycin is particularly useful in pediatrics, and further research may improve dosing practices altogether.

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Data availability

The datasets generated and analysed during the current study are available from the corresponding author on request.

Abbreviations

α1-agp:

α1-Acid glycoprotein

AUC24h :

24-h area under de curve

Cmax :

Maximum plasma concentration

ECOFF:

Epidemiological cut-off

EUCAST:

European Committee on Antimicrobial Susceptibility Testing

fC50ss :

Mid free drug concentration at steady state

FDA:

Food and Drug Administration

fT > MIC:

Fraction of dosing interval free drug concentration is above the minimum inhibitory concentration (%)

HIV:

Human immunodeficiency virus

HPLC:

High performance liquid chromatography

LC:

Liquid chromatography

MIC:

Minimum inhibitory concentration

MIPD:

Model-informed precision dosing

MS/MS:

Tandem mass spectrometry

PD:

Pharmacodynamic/pharmacodynamics

PK:

Pharmacokinetic/pharmacokinetics

PopPK:

Population pharmacokinetics

QD:

Once daily

QID:

Four times a day

TID:

Three times a day

UPLC:

Ultra high performance liquid chromatography

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Acknowledgements

The authors would like to thank the residents and nurses of the Pediatrics division at Hospital Central “Dr Ignacio Morones Prieto” for their support during patient recruitment, as well as the patients and their family members who agreed to participate in the study.

Funding

The present study was supported by Mexico’s Office of Public Education through the government program: “Programa para el Desarrollo Profesional Docente, PRODEP” (511-6/2020-8585). A master’s fellowship was granted to Rodrigo Velarde-Salcedo by the Technological Research Council of Science (CONACyT) from Mexico (Grant 782280).

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Authors and Affiliations

  1. Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, S.L.P., México

    Rodrigo Velarde-Salcedo, Ana Socorro Rodríguez-Báez, Rosa del Carmen Milán-Segovia, Silvia Romano-Moreno & Susanna Edith Medellín-Garibay

  2. Hospital Central “Dr. Ignacio Morones Prieto”, San Luis Potosí, S.L.P., México

    Luis Fernando Pérez-González & Francisco Javier Arriaga-García

Authors
  1. Rodrigo Velarde-Salcedo
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  2. Luis Fernando Pérez-González
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  3. Ana Socorro Rodríguez-Báez
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  4. Francisco Javier Arriaga-García
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  5. Rosa del Carmen Milán-Segovia
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  6. Silvia Romano-Moreno
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  7. Susanna Edith Medellín-Garibay
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Rodrigo Velarde-Salcedo, Susanna Edith Medellín-Garibay, Silvia Romano-Moreno, Rosa del Carmen Milán Segovia, Luis Fernando Pérez-González, Francisco Javier Arriaga García, and Ana Socorro Rodríguez-Báez. The first draft of the manuscript was written by Rodrigo Velarde-Salcedo, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Susanna Edith Medellín-Garibay.

Ethics declarations

Ethics approval

This study was carried out in line with ethical principles of the Declaration of Helsinki. Approval was granted by the Research and Ethics Committee of Hospital Central “Dr. Ignacio Morones Prieto,” SLP, México (Registration number 69-21; August 26th, 2021).

Consent to participate

Written informed consent was obtained from patients’ parents, and informed assent was obtained from patients over 12 years of age.

Competing interests

The authors declare no competing interests.

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Communicated by Peter de Winter

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Velarde-Salcedo, R., Pérez-González, L.F., Rodríguez-Báez, A.S. et al. Model-informed precision dosing of antimicrobial drugs in pediatrics: experiences from a pilot scale program. Eur J Pediatr 182, 4143–4152 (2023). https://doi.org/10.1007/s00431-023-05103-z

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