Predicting Maternal-Fetal Disposition of Fentanyl Following Intravenous and Epidural Administration Using Physiologically Based Pharmacokinetic Modeling

Shum, Sara; Shen, Danny D.; Isoherranen, Nina

doi:10.1124/dmd.121.000612

Cited by 16 publications

(8 citation statements)

References 69 publications

(78 reference statements)

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“…Another area of interest for PBPK modeling is the use of PBPK models to explore drug disposition during pregnancy (Gaohua et al, 2012;Ke et al, 2012;Jing et al, 2017;Shum et al, 2021). There is a great need for reliable PBPK models to predict drug disposition during pregnancy as minority of the drugs given to pregnant women have ever been evaluated in pregnant women for PK or PD changes (Ke et al, 2014a(Ke et al, , 2018Abduljalil and Badhan, 2020).…”

Section: Model Development Applications and Verificationmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

Isoherranen

2024

Drug Metabolism and Disposition

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Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and in academic research. The use of PBPK models is continuously expanding with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug disposition during pregnancy and in organ impairment have increased reflecting the advances in incorporating diverse physiological changes into the models. Due to the expanding computational power and diversity of modeling platforms available, the complexity of PBPK models has also increased. Academic efforts have provided clear advances in better capturing human physiology in PBPK models and incorporating more complex mathematical concepts into PBPK models. Examples of such advances include the segregated gut model with a series of gut compartments allowing modeling of physiological blood flow distribution within an organ and zonation of metabolic enzymes, and series compartment liver models allowing simulations of hepatic clearance for high extraction drugs. Despite these advances in academic research, the progress in assessing model quality and defining model acceptance criteria based on the intended use of the models has not kept pace. This review suggests that awareness of the need for predefined criteria for model acceptance has increased but many manuscripts still lack description of scientific justification and/or rationale for chosen acceptance criteria. As artificial intelligence and machine learning approaches become more broadly accepted, these tools offer promise for development of comprehensive assessment for existing observed data and analysis of model performance.

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Section: Model Development Applications and Verificationmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

Isoherranen

2024

Drug Metabolism and Disposition

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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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“…Physiologically based pharmacokinetic (PBPK) modeling is increasingly used to characterize and predict the effects of physiological changes on drug disposition during pregnancy. [17][18][19] We hypothesized that PBPK modeling can be used to define changes in INH PK during pregnancy. To test this hypothesis, a full PBPK model of INH was developed and verified in a non-pregnant population with defined NAT2 phenotypes.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy

Amaeze,

Isoherranen

2023

Clinical Translational Sci

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Pregnancy can increase the risk of latent tuberculosis infection (LTBI) progression to tuberculosis (TB) disease. Isoniazid (INH) is the preferred preventative treatment for LTBI in pregnancy. INH is mainly cleared by N‐acetyltransferase 2 (NAT2) but the pharmacokinetics (PK) of INH in different NAT2 phenotypes during pregnancy is not well characterized. To address this knowledge gap, we used physiologically based pharmacokinetic (PBPK) modeling to evaluate NAT2 phenotype‐specific effects of pregnancy on INH disposition. A whole‐body PBPK model for INH was developed and verified for non‐pregnant NAT2 fast (FA), intermediate (IA), and slow (SA) acetylators. Model predictive performance was assessed using a drug‐specific model acceptance criterion for mean plasma area under the curve (AUC) and peak plasma concentration (Cmax), and the absolute average fold error (AAFE) for individual plasma concentrations. The verified model was extended to simulate INH disposition during pregnancy in NAT2 SA, IA, and FA populations. A sensitivity analysis was conducted using the verified PBPK model and known changes in INH disposition during pregnancy to determine whether NAT2 activity changes during pregnancy or other INH clearance pathways are altered. This analysis suggested that NAT2 activity is unchanged while other INH clearance pathways increase by ~80% during pregnancy. The model was applied to explore the effect of pregnancy on INH disposition in two ethnic populations with different NAT2 phenotype distributions and with high TB burden. Our PBPK model can be used to predict INH disposition during pregnancy in diverse populations and expanded to other drugs cleared by NAT2 during pregnancy.

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Predicting Maternal-Fetal Disposition of Fentanyl Following Intravenous and Epidural Administration Using Physiologically Based Pharmacokinetic Modeling

Cited by 16 publications

References 69 publications

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy

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