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van Hoogdalem MW, Johnson TN, McPhail BT, et al. Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome. Clin Pharmacol Ther. 2021;111(2):496-508doi: 10.1002/cpt.2458.
van Hoogdalem, M. W., Johnson, T. N., McPhail, B. T., Kamatkar, S., Wexelblatt, S. L., Ward, L. P., Christians, U., Akinbi, H. T., Vinks, A. A., & Mizuno, T. (2022). Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome. Clinical pharmacology and therapeutics, 111(2), 496-508. https://doi.org/10.1002/cpt.2458
van Hoogdalem, Matthijs W, et al. "Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome." Clinical pharmacology and therapeutics vol. 111,2 (2022): 496-508. doi: https://doi.org/10.1002/cpt.2458
van Hoogdalem MW, Johnson TN, McPhail BT, Kamatkar S, Wexelblatt SL, Ward LP, Christians U, Akinbi HT, Vinks AA, Mizuno T. Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome. Clin Pharmacol Ther. 2022 Feb;111(2):496-508. doi: 10.1002/cpt.2458. Epub 2021 Nov 21. PMID: 34679189; PMCID: PMC8748288.
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Clin Pharmacol Ther. 2022 Feb;111(2):496-508. doi: 10.1002/cpt.2458. Epub 2021 Nov 21.

Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome.

Clinical pharmacology and therapeutics

Matthijs W van Hoogdalem, Trevor N Johnson, Brooks T McPhail, Suyog Kamatkar, Scott L Wexelblatt, Laura P Ward, Uwe Christians, Henry T Akinbi, Alexander A Vinks, Tomoyuki Mizuno

Affiliations

  1. Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  2. James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
  3. Certara UK Limited, Sheffield, UK.
  4. School of Medicine Greenville, University of South Carolina, Greenville, South Carolina, USA.
  5. Division of Neonatology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  6. Community Hospital East, Indianapolis, Indiana, USA.
  7. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
  8. Center for Addiction Research, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
  9. iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado, USA.

PMID: 34679189 PMCID: PMC8748288 DOI: 10.1002/cpt.2458

Abstract

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC

© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.

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