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Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome

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Abstract

Background and Objective

Buprenorphine has been shown to be effective in treating infants with neonatal opioid withdrawal syndrome. However, an evidence-based buprenorphine dosing strategy has not been established in the treatment of neonatal opioid withdrawal syndrome because of a lack of exposure–response data. The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic model to predict buprenorphine treatment outcomes in newborns with neonatal opioid withdrawal syndrome.

Methods

Clinical data were obtained from 19 newborns with a median (range) gestational age of 37 (34–41) weeks enrolled in a pilot pharmacokinetic study of buprenorphine. Sparse blood sampling, comprising three specimens obtained around the second dose of buprenorphine, was performed using heel sticks with dried blood spot technology. Standardized neonatal opioid withdrawal syndrome severity scores (Finnegan scores) were collected every 3–4 h based on symptoms by bedside nursing staff. Mean Finnegan scores were used as a pharmacodynamic marker in the exposure–response modeling. The blood concentration–Finnegan score relationship was described using a physiologic indirect response model with inclusion of natural disease remission.

Results

A total of 52 buprenorphine blood concentrations and 780 mean Finnegan scores were available for the pharmacokinetic/pharmacodynamic modeling and exposure–response analysis. A one-compartment model with first-order absorption adequately described the pharmacokinetic data. The buprenorphine blood concentration at 50% of maximum effect for the inhibition of disease progression was 0.77 ng/mL (95% confidence interval 0.32–1.2). The inclusion of natural disease remission described as a function of postnatal age significantly improved the model fit.

Conclusions

A buprenorphine pharmacokinetic/pharmacodynamic model was successfully developed. The model could facilitate model-informed optimization of the buprenorphine dosing regimen in the treatment of neonatal opioid withdrawal syndrome.

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Acknowledgements

We thank Nieko Punt (Medimatics, Maastricht, the Netherlands) for his scientific inputs.

Author information

Author notes

  1. Brooks T. McPhail

    Present address: School of Medicine Greenville, University of South Carolina, Greenville, SC, USA

  2. Suyog Kamatkar

    Present address: Community Hospital East, Indianapolis, IN, USA

Authors and Affiliations

  1. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA

    Tomoyuki Mizuno, Brooks T. McPhail & Alexander A. Vinks

  2. Division of Neonatology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Suyog Kamatkar, Scott Wexelblatt, Laura Ward & Henry T. Akinbi

  3. iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA

    Uwe Christians

  4. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Tomoyuki Mizuno, Scott Wexelblatt, Laura Ward, Henry T. Akinbi & Alexander A. Vinks

  5. Center for Addiction Research, University of Cincinnati College of Medicine, 3230 Eden Ave, Cincinnati, OH, 45267, USA

    Tomoyuki Mizuno, Scott Wexelblatt & Alexander A. Vinks

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  1. Tomoyuki Mizuno
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Corresponding author

Correspondence to Tomoyuki Mizuno.

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Funding

Brooks T. McPhail was supported by a Eunice Kennedy Shriver National Institute of Child Health and Human Development training Grant (5T32HD069054).

Conflict of interest

Scott Wexelblatt has received a research grant from Chiesi Pharmaceuticals and a consulting fee from Braeburn Pharmaceuticals. He is also on a speaker bureau to discuss treatment options for NOWS. These payments had no effect on this paper or results. Tomoyuki Mizuno, Brooks T. McPhail, Suyog Kamatkar, Laura Ward, Uwe Christians, Henry T. Akinbi, and Alexander A. Vinks have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Not applicable.

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Author contributions

TM, BTM, SK, SW, LW, UC, HTA, and AAV wrote the manuscript and designed the research. TM, BTM, SK, LW, UC, HTA, and AAV performed the research and analyzed the data.

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Mizuno, T., McPhail, B.T., Kamatkar, S. et al. Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome. Clin Pharmacokinet 60, 249–259 (2021). https://doi.org/10.1007/s40262-020-00939-2

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  • DOI: https://doi.org/10.1007/s40262-020-00939-2

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