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Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on

Yumi Cleary1,2, Heidemarie Kletzl3, Paul Grimsey4

  • 1Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. yumi.cleary@roche.com.

Clinical Pharmacokinetics
|May 6, 2023
PubMed
Abstract

Insights

This study derived in vivo flavin-containing monooxygenase 3 (FMO3) ontogeny in children using risdiplam pharmacokinetic data. The findings improve predictions of drug metabolism and interactions for children, particularly for FMO3 substrates.

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Pediatric Pharmacology
  • Pharmacometrics

Background:

  • Spinal muscular atrophy (SMA) is treated with risdiplam, which is metabolized by flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 3A (CYP3A).
  • Accurate prediction of risdiplam pharmacokinetics (PK) and drug-drug interactions (DDIs) in children requires understanding FMO3 ontogeny (developmental changes in enzyme activity).
  • Existing in vitro FMO3 ontogeny data lack robustness for in vivo application in pediatric populations.

Purpose of the Study:

  • To estimate in vivo FMO3 ontogeny in children using mechanistic population pharmacokinetic (Mech-PPK) modeling of risdiplam.
  • To assess the impact of the derived FMO3 ontogeny on predicting risdiplam PK in children.
  • To investigate the influence of FMO3 ontogeny on potential drug-drug interactions (DDIs) in pediatric populations.

Main Methods:

  • Integrated population and physiologically based pharmacokinetic (PPK and PBPK) models into a Mech-PPK framework.
  • Analyzed 10,205 risdiplam plasma concentration-time data points from 525 subjects aged 2 months to 61 years.
  • Simulated DDIs for dual CYP3A-FMO3 substrates using various metabolic fraction ratios.

Main Results:

  • All models predicted significantly higher FMO3 activity in children, peaking around age 2 years (threefold difference vs. adults).
  • The derived in vivo FMO3 ontogeny function improved risdiplam PK prediction in children compared to in vitro data.
  • Simulations indicated comparable or reduced CYP3A-victim DDI risk in children for dual substrates, with risdiplam showing minimal DDI risk.

Conclusions:

  • Mechanistic population PK modeling successfully estimated in vivo FMO3 ontogeny in a large pediatric cohort.
  • This is the first study to establish in vivo FMO3 ontogeny using a population approach across a wide age range.
  • The derived FMO3 ontogeny function is crucial for predicting PK and DDIs of FMO3 substrates in children.

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