Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population

Abduljalil, Khaled; Pan, Xian; Pansari, Amita; Jamei, Masoud; Johnson, Trevor N.

doi:10.1007/s40262-019-00827-4

Cited by 43 publications

(38 citation statements)

References 87 publications

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“…For the most part, analyses of the accuracy of PBPK modeling for predicting the PK of smallmolecule drugs in preterm infants report AUC and CL as primary outcomes of interest. 59 However, it is the trough concentrations and the half-life that drive FIP dose selection for mAbs, especially those targeted against infectious antigens. 3,19,21 For these products, clinicians seek a dosing regimen that sustains a trough concentration above a target value.…”

Section: Discussionmentioning

confidence: 99%

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Malik

Edginton

2019

The Journal of Clinical Pharma

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An understanding of pediatric pharmacokinetics (PK) is essential for first‐in‐pediatric dose selection and clinical trial design. At present, there is no reliable way to scale the PK of monoclonal antibodies and immunoglobulin G drug products from adults to young children or to premature infants—a vulnerable population with a rapidly growing drug development pipeline. In this work, pediatric physiologically based PK models are constructed in PK‐Sim and Mobi to explore the PK of pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin in preterm infants. In addition to considering ontogeny in pediatric organ volumes, organ composition, blood flow rates, and hematocrit, advanced ontogeny is applied for 3 key parameters: capillary surface area, hematopoietic cell concentration, and lymph flow rate. The role and importance of each parameter for determining pediatric clearance (CL) and volume of distribution at steady state (VSS) are quantitatively assessed with a local sensitivity analysis. In addition, the uncertainty around parameters with limited information in pediatrics is addressed (eg, free neonatal Fc receptor concentration). The full ontogeny parameterization yields pediatric PK predictions that are within 1.5‐fold prediction error >90% of the time for preterm infants, with an absolute average fold error of 1.05. This result suggests that many of the key factors related to ontogeny are appropriately addressed. Overall, this study makes a first step toward developing a platform pediatric physiologically based PK model for monoclonal antibodies and immunoglobulin G drug products by solidifying existing parameterizations, integrating new concepts, and drawing attention to unmet needs for physiologic knowledge in children.

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Section: Discussionmentioning

confidence: 99%

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Malik

Edginton

2019

The Journal of Clinical Pharma

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“…We read with interest the two recent articles in Clinical Pharmacokinetcs by Abduljalil et al describing a preterm physiologically based pharmacokinetic model and evaluate its performance for eight hepatically and renally cleared drugs [ 1 , 2 ].…”

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confidence: 99%

Comment on: "Preterm Physiologically Based Pharmacokinetic Model, Part I and Part II”

et al. 2021

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“…In this study, Pgp expression in pre-term neonates is assumed to be at 34% and at term 41% of adult expression and fully matured at 6 months of age according to immunohistochemistry data in postmortem human BBB tissue [9]. Parameters specific for neonates were extracted from the population reported in Simcyp V19 and CSF production rate in neonates was assumed to be 10 mL/h [67,68,71,72]. Drug-specific model parameters for morphine and morphine-6-glucuronide are listed in table 1 and were derived from literature sources or in vitro data generated in this study.…”

Section: Development Of a Pbpk Model For Morphine And Morphine-6-glucmentioning

confidence: 99%

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Verscheijden

Litjens²,

Koenderink

et al. 2021

PLoS Comput Biol

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Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

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Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population

Cited by 43 publications

References 87 publications

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Comment on: "Preterm Physiologically Based Pharmacokinetic Model, Part I and Part II”

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

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