Tomoyuki Mizuno1,2,3, Brooks T McPhail4,5, Suyog Kamatkar6,7, Scott Wexelblatt6,8,9, Laura Ward6,8, Uwe Christians10, Henry T Akinbi6,8, Alexander A Vinks4,8,9. 1. Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA. tomoyuki.mizuno@cchmc.org. 2. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. tomoyuki.mizuno@cchmc.org. 3. Center for Addiction Research, University of Cincinnati College of Medicine, 3230 Eden Ave, Cincinnati, OH, 45267, USA. tomoyuki.mizuno@cchmc.org. 4. Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA. 5. School of Medicine Greenville, University of South Carolina, Greenville, SC, USA. 6. Division of Neonatology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 7. Community Hospital East, Indianapolis, IN, USA. 8. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. 9. Center for Addiction Research, University of Cincinnati College of Medicine, 3230 Eden Ave, Cincinnati, OH, 45267, USA. 10. iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA.
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.
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.
Authors: Walter K Kraft; Susan C Adeniyi-Jones; Inna Chervoneva; Jay S Greenspan; Diane Abatemarco; Karol Kaltenbach; Michelle E Ehrlich Journal: N Engl J Med Date: 2017-05-04 Impact factor: 91.245
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Authors: Jason R Wiles; Barbara Isemann; Tomoyuki Mizuno; Meredith E Tabangin; Laura P Ward; Henry Akinbi; Alexander A Vinks Journal: J Pediatr Date: 2015-09-11 Impact factor: 4.406
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Authors: 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 Journal: Clin Pharmacol Ther Date: 2021-11-21 Impact factor: 6.903
Authors: Rena Eudy-Byrne; Nicole Zane; Susan C Adeniyi-Jones; Marc R Gastonguay; Ana Ruiz-Garcia; Gagan Kaushal; Walter K Kraft Journal: Clin Transl Sci Date: 2021-09-16 Impact factor: 4.438