ArticleClinical pharmacokinetics2023
Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.
Article in Clinical pharmacokinetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 5 registered trials, which are not on this map. Cited by 8 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Single-Center, Randomized, Investigator/Subject-Blind, Adaptive Single-Ascending-Dose(SAD), Placebo-Controlled, Parallel Study to Investigate the Safety, Tolerability, Pharmacokinetics (Including the Effect of Food and the Effect of Itraconazole on the Pharmacokinetics of a Single Oral Dose of RO7034067), and Pharmacodynamics of RO7034067 Following Oral Administration in Healthy Subjects
A Two Part Seamless, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients
A Two Part Seamless, Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Infants With Type 1 Spinal Muscular Atrophy
An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy
A Phase I, 2-Part, Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam and the Effect of Risdiplam on the Pharmacokinetics of Midazolam Following Oral Administration in Healthy Participants
Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations.Journal of pharmacokinetics and pharmacodynamics · 2024Trial
- Population Physiologically-Based Pharmacokinetic Modeling to Determine Ontogeny: A Quantitative Clinical Pharmacology Example in Pediatric Rare Disease.CPT: pharmacometrics & systems pharmacology · 2026Review
- Pharmacokinetics of therapies approved for spinal muscular atrophy: A narrative review of current evidence.The Journal of international medical research · 2025Review
- State-of-the-Art on Model-Informed Drug Development Approaches for Pediatric Rare Diseases.CPT: pharmacometrics & systems pharmacology · 2025Review
- Article
- Clozapine Drug-Drug Interactions and Individualized Dosing in Bipolar Disorder: A Model-Informed Precision Dosing Approach.Drug design, development and therapy · 2025Article
- Population pharmacokinetics modelling to predict DDI from zopiclone on clozapine in schizophrenia patients.Frontiers in psychiatry · 2025Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectiveSpinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (Evrysdi
methodsPopulation and physiologically based PK (PPK and PBPK) modelling conducted during the development of risdiplam were integrated into a mechanistic PPK (Mech-PPK) model to estimate in vivo FMO3 ontogeny. A total of 10,205 risdiplam plasma concentration-time data from 525 subjects aged 2 months-61 years were included. Six different structural models were examined to describe the in vivo FMO3 ontogeny. Impact of the newly estimated FMO3 ontogeny on predictions of drug-drug interaction (DDI) in children was investigated by simulations for dual CYP3A-FMO3 substrates including risdiplam and theoretical substrates covering a range of metabolic fractions (fm) of CYP3A and FMO3 (fm
resultsAll six models consistently predicted higher FMO3 expression/activity in children, reaching a maximum at the age of 2 years with an approximately threefold difference compared with adults. Different trajectories of FMO3 ontogeny in infants < 4 months of age were predicted by the six models, likely due to limited observations for this age range. Use of this in vivo FMO3 ontogeny function improved prediction of risdiplam PK in children compared to in vitro FMO3 ontogeny functions. The simulations of theoretical dual CYP3A-FMO3 substrates predicted comparable or decreased CYP3A-victim DDI propensity in children compared to adults across the range of fm values. Refinement of FMO3 ontogeny in the risdiplam model had no impact on the previously predicted low CYP3A-victim or -perpetrator DDI risk of risdiplam in children.
conclusionMech-PPK modelling successfully estimated in vivo FMO3 ontogeny from risdiplam data collected from 525 subjects aged 2 months-61 years. To our knowledge, this is the first investigation of in vivo FMO3 ontogeny by population approach using comprehensive data covering a wide age range. Derivation of a robust in vivo FMO3 ontogeny function has significant implications on the prospective prediction of PK and DDI in children for other FMO3 substrates in the future, as illustrated in the current study for FMO3 and/or dual CYP3A-FMO3 substrates. CLINICAL TRIAL REGISTRY NUMBERS: NCT02633709, NCT03032172, NCT02908685, NCT02913482, NCT03988907.
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Registered trials
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.