Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study

Badhan, Raj; Gittins, Rosalind

doi:10.1016/j.jsat.2021.108521

Cited by 11 publications

(14 citation statements)

References 85 publications

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“…hCOs were exposed to 1 µM methadone, a concentration that falls within the 0.8–1.7 µM range typically reported in the plasma of pregnant women [ 7 , 38 – 41 ]. Studies support extensive materno-fetal transfer of methadone, with evidence from both humans and rats indicating accumulation of the drug in fetal tissues and cord blood throughout gestation [ 4 , 7 , 8 ]. At dosages required to reach withdrawal relief (100–180 mg) during pregnancy, trough concentrations of methadone in cord blood are predicted to reach the maternal reference range used to establish our treatment paradigm [ 4 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies support extensive materno-fetal transfer of methadone, with evidence from both humans and rats indicating accumulation of the drug in fetal tissues and cord blood throughout gestation [ 4 , 7 , 8 ]. At dosages required to reach withdrawal relief (100–180 mg) during pregnancy, trough concentrations of methadone in cord blood are predicted to reach the maternal reference range used to establish our treatment paradigm [ 4 , 8 ]. Therefore, exposing hCOs to this concentration for 50 days beginning just after neural induction, allowed us to assess the direct effect of methadone on neural growth and maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its utility in adults, methadone’s ability to readily enter fetal circulation and accumulate in neural tissue has led to concerns regarding its effects on brain development in utero [ 4 , 7 , 8 ]. Clinically, prenatal methadone exposure is linked with increased incidence and severity of Neonatal Abstinence Syndrome (NAS), characterized by central nervous system hyperirritability and autonomic nervous system dysfunction [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Methadone alters transcriptional programs associated with synapse formation in human cortical organoids

et al. 2023

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Opioid use disorder (OUD) among pregnant women has become an epidemic in the United States. Pharmacological interventions for maternal OUD most commonly involve methadone, a synthetic opioid analgesic that attenuates withdrawal symptoms and behaviors linked with drug addiction. However, evidence of methadone’s ability to readily accumulate in neural tissue, and cause long-term neurocognitive sequelae, has led to concerns regarding its effect on prenatal brain development. We utilized human cortical organoid (hCO) technology to probe how this drug impacts the earliest mechanisms of cortico-genesis. Bulk mRNA sequencing of 2-month-old hCOs chronically treated with a clinically relevant dose of 1 μM methadone for 50 days revealed a robust transcriptional response to methadone associated with functional components of the synapse, the underlying extracellular matrix (ECM), and cilia. Co-expression network and predictive protein-protein interaction analyses demonstrated that these changes occurred in concert, centered around a regulatory axis of growth factors, developmental signaling pathways, and matricellular proteins (MCPs). TGFβ1 was identified as an upstream regulator of this network and appeared as part of a highly interconnected cluster of MCPs, of which thrombospondin 1 (TSP1) was most prominently downregulated and exhibited dose-dependent reductions in protein levels. These results demonstrate that methadone exposure during early cortical development alters transcriptional programs associated with synaptogenesis, and that these changes arise by functionally modulating extra-synaptic molecular mechanisms in the ECM and cilia. Our findings provide novel insight into the molecular underpinnings of methadone’s putative effect on cognitive and behavioral development and a basis for improving interventions for maternal opioid addiction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methadone alters transcriptional programs associated with synapse formation in human cortical organoids

et al. 2023

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“…Other oral, IV, or subcutaneous opioid PBPK models exist for morphine [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], alfentanil [ 49 , 50 , 51 , 52 ], remifentanil [ 53 , 54 , 55 ], sufentanil [ 56 ], tramadol [ 56 , 57 , 58 , 59 , 60 , 61 ], fentanyl [ 62 , 63 , 64 , 65 , 66 , 67 ], oxycodone [ 40 , 64 , 68 , 69 ], buprenorphine [ 64 , 70 , 71 , 72 , 73 , 74 , 75 ], codeine [ 76 , 77 ], methadone [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ], and carfentanil to predict drug-drug interactions and drug disposition in the plasma and various ...…”

Section: Illegally Used Drugsmentioning

confidence: 99%

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

Fairman

Choi

Gonnabathula

et al. 2023

Toxics

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A physiologically-based pharmacokinetic (PBPK) model represents the structural components of the body with physiologically relevant compartments connected via blood flow rates described by mathematical equations to determine drug disposition. PBPK models are used in the pharmaceutical sector for drug development, precision medicine, and the chemical industry to predict safe levels of exposure during the registration of chemical substances. However, one area of application where PBPK models have been scarcely used is forensic science. In this review, we give an overview of PBPK models successfully developed for several illicit drugs and environmental chemicals that could be applied for forensic interpretation, highlighting the gaps, uncertainties, and limitations.

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“…A range of software companies offers PBPK modelling platforms [ 25 ], including paediatrics, of which the Simcyp™ Simulator is widely used to predict drug performance from virtual population groups, including paediatrics [ 26 , 27 ], pregnancy [ 28 , 29 , 30 ] and specialised disease states such as oncology [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

et al. 2023

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The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.

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Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study

Cited by 11 publications

References 85 publications

Methadone alters transcriptional programs associated with synapse formation in human cortical organoids

Methadone alters transcriptional programs associated with synapse formation in human cortical organoids

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

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