Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects

Maharaj, Anil; González, Daniel; Cohen‐Wolkowiez, Michael; Hornik, Christoph P.; Edginton, Andrea N.

doi:10.1007/s40262-017-0576-7

Cited by 26 publications

(12 citation statements)

References 56 publications

(93 reference statements)

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“…Although the sensitivity analyses indicated that P‐gp might not play a significant role in determining PK parameters of vincristine, the ontogeny of P‐gp was also considered, as protein expression of P‐gp is ~60% and 80% of adult levels in infants and children, respectively . We also considered the binding of vincristine to the plasma protein α‐1‐acid glycoprotein (AAG), as AAG levels increase with age . Because vincristine is not extensively bound to AAG ( f u 0.51) and AAG levels are lower in young children, this was not expected to explain the distribution of vincristine in children .…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Lee

Zane

Veal

et al. 2019

CPT Pharmacom & Syst Pharma

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Vincristine is a cytotoxic chemotherapeutic agent used as first‐line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by CYP3A4 and CYP3A5 and via hepatic (biliary) efflux mediated by P‐glycoprotein (P‐gp) transporter. Bottom‐up physiologically based pharmacokinetic (PBPK) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by CYP3A4/5, efflux by P‐gp, and intracellular binding to β‐tubulin. The adult and pediatric PBPK models predicted pharmacokinetics (PK) within twofold of the observed PK parameters (area under the curve, terminal half‐life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9‐fold) pediatric expression of β‐tubulin relative to adult improved predictions of vincristine PKs. To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric PBPK model. Utilizing this PBPK modeling approach, safe and effective doses of vincristine could be predicted.

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Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Lee

Zane

Veal

et al. 2019

CPT Pharmacom & Syst Pharma

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“…In order to adequately apply PBPK modeling to children for drugs eliminated through specific elimination pathways, a proper implementation of the ontogeny of these pathways in the model is needed. Several articles have been published identifying the ontogeny of active processes such as phase 1 and phase 2 metabolizing enzymes and, to a lesser extent, transporters as well as passive processes such as glomerular filtration rate (GFR) and plasma proteins . Ontogeny information can originate from various sources such as in the form of (semi)quantitative mRNA expression or in vitro activity data .…”

Section: Application Of Pbpk In Pediatric Researchmentioning

confidence: 99%

“…Several articles have been published identifying the ontogeny of active processes such as phase 1 and phase 2 metabolizing enzymes 14,15 and, to a lesser extent, transporters [16][17][18] as well as passive processes such as glomerular filtration rate (GFR) 19 and plasma proteins. 20 Ontogeny information can originate from various sources such as in the form of (semi)quantitative mRNA expression 21 or in vitro activity data. 22 Ontogeny information can also be derived by deconvolution of in vivo pharmacokinetic data in the case that information for all but 1 relevant clearance ontogeny is available.…”

Section: Established Ontogeny Functionsmentioning

confidence: 99%

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Ince

Solodenko

Frechen

et al. 2019

The Journal of Clinical Pharma

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Food and Drug Administration submissions of physiologically based pharmacokinetic (PBPK) modeling and simulation of small‐molecule drugs document the relevance of pediatric drug development and, in particular, information on dosing strategies in children. The most relevant prerequisite for reliable PBPK‐based translation of adult pharmacokinetics of a small molecule to children is knowledge of the drug‐specific absorption, distribution, metabolism, and elimination (ADME) processes in adults together with existing information about ontogeny of ADME processes relevant for the drug. All mechanisms driving a drug's clearance are of specific importance. For other drug modalities, our knowledge of ADME processes and ontogeny is still limited. More research is required, for example, to understand why some therapeutic proteins show complex differences in pharmacokinetics between adults and children, whereas other proteins seem to follow simple allometric scaling rules. Ontogeny information originates from various sources, such as (semi)quantitative mRNA expression, in vitro activity data, and deconvolution of in vivo pharmacokinetic data. The workflow for pediatric predictions is well described in several articles documenting successful translation from adults to children. The technical hurdles for PBPK modeling are low. State‐of‐the‐art PBPK modeling software tools provide integrated pediatric translation workflows. For example, PK‐Sim and MoBi are freely available as fully transparent open‐source software via Open Systems Pharmacology (OSP). With the latest 2019 software release, version 8.0, OSP even provides a fully integrated technical framework for the qualification (and requalification) of any specific intended PBPK use in line with Food and Drug Administration and European Medicines Agency PBPK guidance. Qualification packages for pediatric translation are available on the OSP platform.

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“…14 For the organs in which no data were available, the same percentage of cardiac output in adults was assumed. The ontogeny function of alpha-1-acid glycoprotein (AAG) was taken from Maharaj et al 29 using Eq. 2 and assuming a coefficient of variation of 25%.…”

Section: Pediatric Pbpk Modelmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Watt

Cohen‐Wolkowiez

Barrett

et al. 2018

CPT Pharmacom & Syst Pharma

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Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

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Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects

Abstract: The current investigation depicts a proficient modality for estimation of protein binding in pediatrics and will, therefore, aid in reducing uncertainty associated with pediatric pharmacokinetic predictions.

Cited by 26 publications

References 56 publications

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

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