Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioi
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ORIGINAL RESEARCH ARTICLE
Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome Tomoyuki Mizuno1,4,7 · Brooks T. McPhail1,5 · Suyog Kamatkar2,6 · Scott Wexelblatt2,4,7 · Laura Ward2,4 · Uwe Christians3 · Henry T. Akinbi2,4 · Alexander A. Vinks1,4,7
© Springer Nature Switzerland AG 2020
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.
1 Introduction The opioid epidemic in the USA has resulted in a more than five-fold increase in neonatal opioid withdrawal syndrome (NOWS) incidence during 2000–2014, reaching 14.4 per 1000 births in 2014 [1]. Newborns experience a range in severity of symptoms of withdrawal after birth, which is Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00939-2) contains supplementary material, which is available to authorized users. * Tomoyuki Mizuno [email protected] Extended author information available on the last page of the article
referred to as NOWS. Newb
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