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Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People: A Population Pharmacokinetic Analysis

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Abstract

Introduction

Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients.

Methods

A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80–95] years, bodyweight 66.4 [49.3–110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target.

Results

A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25–75th percentiles 8.2–12.7] and 8.13 [6.3–9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] <8 mg/L; 31.3 [q6h] and 7.6% [q8h] >12 mg/L).

Conclusion

A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens.

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Acknowledgements

We greatly acknowledge K. Hagoort for editorial assistance.

Author information

Author notes

  1. L. T. van der Heijden and P. Mian contributed equally.

Authors and Affiliations

  1. Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    L. T. van der Heijden, P. Mian & D. Tibboel

  2. Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    L. T. van der Heijden

  3. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands

    P. Mian

  4. Pharmacy Department, University Hospitals Leuven, Leuven, Belgium

    J. Hias, L. Van der Linden, K. Walgraeve & I. Spriet

  5. Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, The Netherlands

    B. C. M. de Winter, B. C. P. Koch & K. Allegaert

  6. Department of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium

    J. Tournoy & J. Flamaing

  7. Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium

    J. Tournoy & J. Flamaing

  8. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    L. Van der Linden, K. Allegaert & I. Spriet

  9. Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    K. Allegaert

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  1. L. T. van der Heijden
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Corresponding author

Correspondence to P. Mian.

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Funding

All authors declare that no funding for this project has been received.

Conflict of interest

All authors declare no conflicts of interest.

Ethics approval

This study was conducted at the University Hospitals Leuven, Belgium, following approval by the medical ethics committee of UZ Leuven (EUDRACT 2015-004217-24).

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Not applicable.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Available upon request to the corresponding author.

Author contributions

LvdH and PM wrote the manuscript; LvdH, PM, LvdL, JH, BK, BdW, DT, JT, JF, KW, and IS edited the manuscript; LvdH and PM provided graphics for the manuscript; LvdH, PM, KA, BK and BdW performed research for the manuscript; LvdH, PM, KA, IS, BK and BdW designed the research; and IS, KA, BK and BdW supervised the research. All authors read and approved the final version of the paper.

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van der Heijden, L.T., Mian, P., Hias, J. et al. Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People: A Population Pharmacokinetic Analysis. Drugs Aging 39, 83–95 (2022). https://doi.org/10.1007/s40266-021-00912-z

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