Physiologically Based Pharmacokinetic (PBPK) Modeling in Children

Barrett, Jeffrey S.; Alberighi, Ornella Della Casa; Läer, Stephanie; Meibohm, Bernd

doi:10.1038/clpt.2012.64

Cited by 161 publications

(178 citation statements)

References 73 publications

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“…Several groups reviewed the use of PBPK in pediatric drug development and research, with various versions of workflow being proposed to predict drug PK in pediatrics using PBPK (Barrett et al, 2012;Leong et al, 2012;Jiang et al, 2013;Maharaj and Edginton, 2014;Willmann et al, 2014). All proposals articulate the importance of establishing/ verifying an adult PBPK model, followed by utilizing the most up-todate pediatric physiology models to prospectively predict drug PK in subjects of different pediatric age groups.…”

Section: Discussionmentioning

confidence: 99%

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

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Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twicedaily regimen, different once-daily dosing regimens for treatmentnaïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

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Section: Discussionmentioning

confidence: 99%

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

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show abstract

“…Additional advantages include the incorporation of compound-related and physiological information which can aid in predicting formulation performance or bioequivalence of products as well as dose or route of administration effects [94,96]. PBPK tools are then useful in the design of paediatric clinical studies, particularly with H. K. Batchelor & J. F. Marriott reference to sampling times and the number of subjects required.…”

Section: Physiologically Based Pharmacokinetic Modellingmentioning

confidence: 99%

“…A further limitation of PBPK modelling lies in the appropriate validation (particularly statistical) of such models [89,91]. There are several excellent reviews on PBPK models in paediatric populations and the reader is directed to these for further information [92,94,95].…”

Section: Physiologically Based Pharmacokinetic Modellingmentioning

confidence: 99%

Paediatric pharmacokinetics: key considerations

Batchelor

Marriott

2015

Brit J Clinical Pharma

210

144

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A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.

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“…OATP1B1 protein expression showed a pattern consistent with ontogeny category 2, with no association found between protein expressions across ages. Further understanding of the ontogeny of drug disposition pathways, including transport proteins, will contribute to the scientific basis for rational approaches to the improvement of pharmacotherapy in young children, including the currently widely used physiologically based modeling and simulation approaches (Laer et al, 2009;Barrett et al, 2012).…”

Section: Ontogeny Of Organic Anion Transporting Polypeptide In Liver mentioning

confidence: 99%

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

Thomson

Hines

Schuetz

2016

Drug Metabolism and Disposition

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Determining appropriate pharmacotherapy in young children can be challenging due to uncertainties in the development of drug disposition pathways. With knowledge of the ontogeny of drugmetabolizing enzymes and an emerging focus on drug transporters, the developmental pattern of the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3 was assessed by relative protein quantification using Western blotting in 80 human pediatric liver specimens covering an age range from 9 days to 12 years. OATP1B3 exhibited high expression at birth, which declined over the first months of life, and then increased again in the preadolescent period. In comparison with children 6-12 years of age, the relative protein expression of highly glycosylated (total) OATP1B3 was 235% (357%) in children <3 months of age, 33% (64%) in the age group from 3 months to 2 years, and 50% (59%) in children 2-6 years of age. The fraction of highly glycosylated to total OATP1B3 increased with age, indicating ontogenic processes not only at the transcriptional level but also at the post-translational level. Similar to OATP1B3, OATP1B1 showed high interindividual variability in relative protein expression but no statistically significant difference among the studied age groups.

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Physiologically Based Pharmacokinetic (PBPK) Modeling in Children

Cited by 161 publications

References 73 publications

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Paediatric pharmacokinetics: key considerations

Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver

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