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Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population.

Methods

Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66–132 μM, while 990 μM was considered as the threshold for toxic concentration.

Results

Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range.

Conclusion

A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

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Authors and Affiliations

  1. Department of Pharmacology & Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain

    Kannan Sridharan

  2. Drug Discovery and Development Centre (H3D), University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Mwila Mulubwa

  3. Salmaniya medical complex, Manama, Kingdom of Bahrain

    Ali Mohamed Qader

  4. College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain

    Ali Mohamed Qader

Authors
  1. Kannan Sridharan
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  2. Mwila Mulubwa
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  3. Ali Mohamed Qader
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Corresponding author

Correspondence to Kannan Sridharan.

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Funding

No funding was received to conduct this study.

Data Availability Statement

The data is available with the corresponding author and shall be shared upon a reasonable request.

Conflict of Interest

Kannan Sridharan, Mwila Mulubwa, and Ali Mohamed Qader do not have any conflict of interest.

Ethics Approval

The study was approved by the Institutional Ethics Committee of Arabian Gulf University (E032-PI-9/21 on 17th October 2021), and Salmaniya Medical Complex (126081121 on 8th November 2021), Kingdom of Bahrain.

Consent to participate

Consent to participate in this research study was obtained from the patients or their legally acceptable representatives.

Consent for publication

Not applicable.

Code availability

Not applicable.

Authors' contributions

KS: Conceived the study idea, wrote proposal, and obtained ethics approval; KS, AMQ: Data collection; MW: Model development; KS, MW: Wrote the first draft of the manuscript; KS, MW, AMQ: revised the drafts and final approval of the final version.

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Sridharan, K., Mulubwa, M. & Qader, A.M. Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults. Eur J Drug Metab Pharmacokinet 48, 531–540 (2023). https://doi.org/10.1007/s13318-023-00841-9

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