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Integration of Ontogeny-Based Changes for Predicting the Exposure of Diphenhydramine in the Pediatric Population: A
Ammara Zamir1, Muhammad Fawad Rasool1, Faleh Alqahtani2
1Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
Insights
A new physiologically based pharmacokinetic (PBPK) model accurately predicts diphenhydramine exposure in children. This model helps optimize pediatric dosing, ensuring safety and effectiveness for children with diphenhydramine.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pediatric Pharmacology
- Computational Modeling
Background:
- Diphenhydramine is an antihistamine used for various conditions, including colds and allergic reactions.
- Accurate systemic exposure prediction in children is crucial due to developmental differences.
- Leveraging adult data to model pediatric pharmacokinetics presents unique challenges.
Purpose of the Study:
- To develop a physiologically based pharmacokinetic (PBPK) model for diphenhydramine in pediatric populations (children and adolescents).
- To predict systemic exposure of diphenhydramine in healthy children and adolescents using adult data.
- To assess the model's accuracy by comparing predicted values with reported pediatric data.
Main Methods:
- Literature data on diphenhydramine pharmacokinetics (PK) and parameters were compiled.
- PK-Sim software (version 11.1) was used to build and refine the PBPK model.
- An adult model was first developed and then extrapolated to pediatric populations for validation.
Main Results:
- The PBPK model demonstrated accuracy within a 2-fold error benchmark for key PK variables (AUC, Cmax, CL).
- Predicted maximal serum/plasma concentration (Cmax) in pediatrics was 3-fold higher than in young adults at a 25 mg dose.
- Findings highlight the need for careful monitoring of diphenhydramine dosage regimens in children.
Conclusions:
- The developed pediatric PBPK model is validated and enhances understanding of developmental PK variations for diphenhydramine.
- This model can aid healthcare professionals in personalizing diphenhydramine dosage regimens for children.
- Improved dosing strategies can promote therapeutic efficacy and minimize adverse effects in pediatric patients.
Background:
Diphenhydramine is an anti-tussive used periodically to treat seasonal colds, contact dermatitis, and anaphylactic reactions. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of diphenhydramine in predicting its systemic exposure among healthy pediatrics (children and adolescents) by leveraging data files from adults (young and elderly).
Methods:
The data profiles comprising serum/plasma concentration over time and parameters related to diphenhydramine were scrutinized via exhaustive literature analysis and consolidated in the PK-Sim software version 11.1. This modeling methodology commences with developing an adult model and then translating it to the pediatrics which compares the predicted concentration-time datasets with the reported values.
Results:
The accuracy of model anticipations was then assessed for each pharmacokinetics (PK) variable, i.e., the area under the curve from 0 to infinity (AUC0-∞), maximal serum/plasma concentration (Cmax), and clearance of the diphenhydramine in plasma (CL) by employing the predicted/observed ratios (Rpre/obs), and average fold error (AFE), which fell within the pre-defined benchmark of 2-fold. The predicted and observed Cmax values for pediatrics were 3-fold greater in comparison to the young adults following a 25 mg dose depicting a need to monitor dosage schedules among children closely.
Conclusions:
These model-based anticipations confirmed the authenticity of the developed pediatric model and enhanced the comprehension of developmental variations on PK of diphenhydramine. This may assist healthcare professionals in ensuring the significance of lifespan applicability in personalized dose regimens, promoting therapeutic efficacy and minimizing side effects in chronic conditions among children.
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