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

Mizuno, Tomoyuki; McPhail, Brooks; Kamatkar, Suyog; Wexelblatt, Scott L.; Ward, Laura P.; Christians, Uwe; Akinbi, Henry T.; Vinks, Alexander A.

doi:10.1007/s40262-020-00939-2

Cited by 9 publications

(24 citation statements)

References 32 publications

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“…Both studies used differential equations to model the disease progression using withdrawal scores as the PD marker, and included the component of natural disease remission in the model building process. 74 , 75 Half‐maximal inhibitory concentration (IC 50 ) estimates obtained from these two studies (0.509 ng/ml and 0.766 ng/ml, respectively) were reasonably close to the previously reported IC 50 value in adults treated for opioid dependence (0.67 ng/ml). 74 , 75 , 107 However, substantial unexplained interpatient variability remained in these PK‐PD models, which undermines their predictive performance and their ability to facilitate model‐informed dosing optimization.…”

Section: Current Dosing and Pharmacometrics‐driven Dosing Optimization In Nowssupporting

confidence: 87%

“… 74 , 75 Half‐maximal inhibitory concentration (IC 50 ) estimates obtained from these two studies (0.509 ng/ml and 0.766 ng/ml, respectively) were reasonably close to the previously reported IC 50 value in adults treated for opioid dependence (0.67 ng/ml). 74 , 75 , 107 However, substantial unexplained interpatient variability remained in these PK‐PD models, which undermines their predictive performance and their ability to facilitate model‐informed dosing optimization. One important reason is that withdrawal scores are generally highly variable because of the subjective nature of the scoring tools, which are also subjective to changes due to intentional nonpharmacologic treatment as well as unintentional environmental cues.…”

Section: Current Dosing and Pharmacometrics‐driven Dosing Optimization In Nowssupporting

confidence: 87%

“… 75 The estimate of standardized clearance (32.6 L/h/70 kg) was also lower than those from previous studies. 75 Such differences from previous models were likely resulted from some important limitations of the PK sampling in this study, where a limited number of PK samples were all taken around the second dose of buprenorphine. As a result of this limited PK sampling time window, insufficient information could be derived regarding terminal phase of buprenorphine PKs and the maturation of buprenorphine clearance over the length of typical treatment duration.…”

Section: Pharmacology and Pharmacokinetics Of First‐line Agents In Nowscontrasting

confidence: 61%

“…Standardized apparent clearance, central volume, and peripheral volume of buprenorphine were estimated to be 203 L/h/70 kg, 142 L/70 kg, and 6350 L/70 kg, which were within 30%-40% of the previously estimated values in the Ng model. 74 Mizuno et al 75 also reported a population PK-PD analysis in patients with NOWS treated with sublingual buprenorphine (52 buprenorphine PK observations from 19 neonates). In contrast to the previous reports, a one-compartment model with first-order absorption was used to describe the PK data, and no age descriptors were included in the PK model after incorporation of allometric scaling.…”

Section: Pharmacology Of Nows Treatmentsmentioning

confidence: 99%

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Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

Tang

Bada

et al. 2021

Clinical Translational Sci

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Section: Current Dosing and Pharmacometrics‐driven Dosing Optimization In Nowssupporting

confidence: 87%

Section: Current Dosing and Pharmacometrics‐driven Dosing Optimization In Nowssupporting

confidence: 87%

Section: Pharmacology and Pharmacokinetics Of First‐line Agents In Nowscontrasting

confidence: 61%

Section: Pharmacology Of Nows Treatmentsmentioning

confidence: 99%

See 2 more Smart Citations

Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

Tang

Bada

et al. 2021

Clinical Translational Sci

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show abstract

“…99,[106][107][108] Pharmacometric models have been used to assess the PD of buprenorphine in neonates with NOWS. Recently, Mizuno et al 109 utilized the Finnegan scores of newborns treated with buprenorphine for NOWS to develop a population PK/PD model. The study used an indirect response model to assess the concentrationresponse relationship between buprenorphine concentrations and Finnegan scores.…”

Section: Pharmacodynamics Of Opioids In Infants With Nowsmentioning

confidence: 99%

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches

McPhail

Emoto

Butler

et al. 2021

The Journal of Clinical Pharma

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Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first‐line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

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

Cited by 9 publications

References 32 publications

Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches

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

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