Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration’s Office of Clinical Pharmacology

Grimstein, Manuela; Yang, Yuching; Zhang, Xinyuan; Grillo, Joseph A.; Huang, Shiew‐Mei; Zineh, Issam; Wang, Yaning

doi:10.1016/j.xphs.2018.10.033

Cited by 258 publications

(256 citation statements)

References 29 publications

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“…Some observed PK data are usually needed to confirm the model prediction in pediatric patients younger than 12 years old because of the uncertainty and knowledge gaps regarding the effects of developmental changes on drug behavior. For pediatric patients younger than 2 years old, a model‐based approach, such as PBPK, after accounting for ontogeny and receptor maturation is considered favorable over an unadjusted allometric scaling approach in deriving dosing regimen …”

Section: Discussionmentioning

confidence: 99%

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Role of Model‐Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling

Liu

et al. 2019

The Journal of Clinical Pharma

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The unique challenges in pediatric drug development require efficient and innovative tools. Model‐informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision‐making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure‐response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the “exposure‐matching” principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug‐drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development.

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Section: Discussionmentioning

confidence: 99%

“…Pediatric PBPK modeling is the second‐highest area (15%) of PBPK application in the regulatory submission . It is mainly used to propose initial dosing recommendations for clinical trials in the investigational new drug stage.…”

Section: Mechanistic Modelsmentioning

confidence: 99%

Role of Model‐Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling

Liu

et al. 2019

The Journal of Clinical Pharma

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“…The ontogeny scaling factors, which are the sigmoidal E max functions, of OAT1/3 were incorporated . To address the argument on whether PBPK modeling is preferred over an allometric scaling approach in predicting the PK for pediatric patients <2 years old, the clearance in the pediatric cohorts was also estimated based on allometry and compared with that predicted using PBPK models . Noteworthy, previous studies have noted that the allometric exponent may be different for various pediatric age groups.…”

Section: Application Of Ontogeny Of Transporters To Midd In Childrenmentioning

confidence: 99%

“…Physiologically based pharmacokinetic (PBPK) modeling is 1 of the mechanistic‐based MIDD tools that has been increasingly incorporated into drug development programs to support submissions to the FDA and the European Medicines Agency . Of all the PBPK analyses that were included in the New Drug Application submissions to the FDA between 2008 and 2017, 60% were utilized to assess enzyme‐mediated drug‐drug interactions (DDIs).…”

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confidence: 99%

“…Of all the PBPK analyses that were included in the New Drug Application submissions to the FDA between 2008 and 2017, 60% were utilized to assess enzyme‐mediated drug‐drug interactions (DDIs). This was followed by 15% of the submissions that supported the evaluation of pediatric‐related issues such as initial dose recommendation for clinical trials and 7% that analyzed transporter‐mediated DDIs . During the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology Meeting in March 2012, some experts expressed concerns regarding the routine use of PBPK modeling in pediatric drug development because pediatric PBPK models still had significant knowledge gaps in areas such as the ontogeny of membrane transporters and thereby may not predict drug exposure well…”

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confidence: 99%

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Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Cheung

Groen

Burckart

et al. 2019

The Journal of Clinical Pharma

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Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age‐dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic‐based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.

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Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

Maharaj

Hornik

et al. 2020

JAMA Pediatr

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; for the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee IMPORTANCE Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. OBJECTIVE To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. DESIGN, SETTING, AND PARTICIPANTS Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. INTERVENTIONS Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. MAIN OUTCOMES AND MEASURES The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. RESULTS For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). CONCLUSIONS AND RELEVANCE This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

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Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration’s Office of Clinical Pharmacology

Cited by 258 publications

References 29 publications

Role of Model‐Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling

Role of Model‐Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling

Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

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