ArticleClinical pharmacology and therapeutics2021
Model-Based Drug-Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy.
Article in Clinical pharmacology and therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 45 citations in OpenAlex.
- Ceftriaxone-ResistantClinical case reports · 2026Article
- Population Physiologically-Based Pharmacokinetic Modeling to Determine Ontogeny: A Quantitative Clinical Pharmacology Example in Pediatric Rare Disease.CPT: pharmacometrics & systems pharmacology · 2026Review
- Virtual Twin-PBPK Modelling: A Step Toward Precision Dosing in Patients with Obesity.The AAPS journal · 2026Article
- State-of-the-Art on Model-Informed Drug Development Approaches for Pediatric Rare Diseases.CPT: pharmacometrics & systems pharmacology · 2025Review
- Pharmacokinetics of therapies approved for spinal muscular atrophy: A narrative review of current evidence.The Journal of international medical research · 2025Review
- Overcoming bioanalytical challenges during the development of risdiplam for the treatment of spinal muscular atrophy.Bioanalysis · 2025Article
- Combining data on the bioavailability of midazolam and physiologically-based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny.CPT: pharmacometrics & systems pharmacology · 2024Article
- Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.Clinical pharmacokinetics · 2024Article
- Article
- Molecular Mechanisms of Medicinal PlantCurrent pharmaceutical design · 2024Article
- Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy.Arquivos de neuro-psiquiatria · 2024Article
- Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients.Clinical and translational science · 2023Article
- Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.Clinical pharmacokinetics · 2023Article
- An open-access data set of pig skin anatomy and physiology for modelling purposes.Database : the journal of biological databases and curation · 2022Article
- Effect of mild or moderate hepatic impairment on the pharmacokinetics of risdiplam.British journal of clinical pharmacology · 2022Article
- Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective.Pharmaceutical research · 2022Review
- Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations.CPT: pharmacometrics & systems pharmacology · 2022Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients ≥2 months old. Risdiplam exhibits time-dependent inhibition of cytochrome P450 (CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug-drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically-based pharmacokinetic (PBPK) model-based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11-fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18-fold lower in vivo CYP3A inactivation constant compared with the in vitro value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK-predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months-18 years was negligible (midazolam AUCR of 1.09-1.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model-based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.