Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics

Hoogdalem, Matthijs W. van; McPhail, Brooks; Hahn, David; Wexelblatt, Scott L.; Akinbi, Henry T.; Vinks, Alexander A.; Mizuno, Tomoyuki

doi:10.1080/17425255.2021.1837112

Cited by 8 publications

(8 citation statements)

References 232 publications

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“…To date, the transport mechanism behind biliary excretion has not been elucidated. 14 Although buprenorphine pharmacokinetics (PK) and pharmacodynamics have been extensively studied in adult populations, clinical data are still very limited in neonates. 14 Physiologicallybased PK (PBPK) modeling has emerged as a suitable approach to characterize and predict the effect of developmental changes on drug disposition in neonates and children.…”

Section: Articlementioning

confidence: 99%

“…14 Although buprenorphine pharmacokinetics (PK) and pharmacodynamics have been extensively studied in adult populations, clinical data are still very limited in neonates. 14 Physiologicallybased PK (PBPK) modeling has emerged as a suitable approach to characterize and predict the effect of developmental changes on drug disposition in neonates and children. 15 PBPK modeling and simulation is a mathematical modeling approach that conjoins human body characteristics with drug physicochemical properties to conceptualize PK behavior.…”

Section: Articlementioning

confidence: 99%

“…50 Moreover, enteral feeding is known to stimulate bile flow. 51 Last, hepatic active transport mechanisms may be underdeveloped in the first days of life, but given that no sinusoidal or canalicular transporters of buprenorphine have been identified, 14 Figure 4 Physiologically-based pharmacokinetic (PBPK) model-predicted and observed concentration-time profiles following sublingual administration of buprenorphine in neonates. Solid line and blue shaded area represent the mean and 5th to 95th percentile range of the virtual twin population (n = 100), respectively.…”

Section: Articlementioning

confidence: 99%

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

Hoogdalem

Johnson²,

McPhail

et al. 2021

Clin Pharma and Therapeutics

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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 0-∞ ), peak concentration (C max ), and time to reach peak concentration (T max ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

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Section: Articlementioning

confidence: 99%

Section: Articlementioning

confidence: 99%

Section: Articlementioning

confidence: 99%

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

Hoogdalem

Johnson²,

McPhail

et al. 2021

Clin Pharma and Therapeutics

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“…NOWS is used when discussing patients exposed to opioids only, while NAS is used to describe withdrawal from opioids as well as other substances. NAS is a result of the abrupt discontinuation of the substances used or abused by the mother during pregnancy and may result from multiple drugs which include, but are not limited to, morphine, heroin, methadone, buprenorphine, prescription opioid analgesics, antidepressants, and anxiolytics ( 6 , 7 ). The withdrawal signs are seen in about 40–80% of the neonates exposed to opioids in utero ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…The adverse effect profile of opioids has stimulated further research into the use of other agents, including benzodiazepines, barbiturates, naloxone, chlorpromazine, and clonidine (7,21,23,24,(29)(30)(31)(32). A Cochrane review of sedatives for NAS treatment recommends opioids as the initial therapy and phenobarbital as the preferred sedative if a sedative is used (29,30).…”

Section: Introductionmentioning

confidence: 99%

Use of Phenobarbital to Treat Neonatal Abstinence Syndrome From Exposure to Single vs. Multiple Substances

et al. 2022

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Drug use in pregnancy is a major public health issue. Intrauterine exposure to opioids alone or in addition to other substances may lead to neonatal abstinence syndrome (NAS). Little consensus exists on optimal therapy, especially for those exposed to multiple drugs. We aim to determine whether the use of opioids alone vs. in combination with phenobarbital will affect short-term neonatal outcomes. This retrospective review of infants admitted to the neonatal intensive care unit (NICU) included newborns ≥35 weeks of gestation exposed to opioids, or multiple substances including opioids, in utero. Treatment with opioids alone, and addition of phenobarbital as initial therapy vs. rescue, was evaluated. Out of 182 newborns, 54 (30%) were exposed to methadone alone vs. 128 (70%) to multiple drugs. Length of stay (LOS) in the hospital was not significantly affected (p = 0.684) by single vs. multiple drug exposure in utero. Treatment of NAS with opioid alone resulted in significantly shorter LOS (27 days), as compared to those treated with opioid and phenobarbital (45 days, p < 0.001). LOS was further prolonged in those treated with phenobarbital as a “rescue” medication in addition to an opioid (49 days, p < 0.0001). There was a significant increase in LOS and duration of opioid treatment for all infants treated with phenobarbital, both in those exposed to opioids alone, and to multiple substances in utero.

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Intrauterine Drug Exposure: Fetal and Postnatal Effects

Baer¹,

Singh²,

Davis³

2024

Avery's Diseases of the Newborn

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Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics

Cited by 8 publications

References 232 publications

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

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

Use of Phenobarbital to Treat Neonatal Abstinence Syndrome From Exposure to Single vs. Multiple Substances

Intrauterine Drug Exposure: Fetal and Postnatal Effects

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