Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.

Background And Objective: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (Evrysdi) increases SMN protein and is approved for the treatment of SMA. Risdiplam has high oral bioavailability and is primarily eliminated through hepatic metabolism by flavin-containing monooxygenase3 (FMO3) and cytochrome P450 (CYP) 3A, by 75% and 20%, respectively. While the FMO3 ontogeny is critical input data for the prediction of risdiplam pharmacokinetics (PK) in children, it was mostly studied in vitro, and robust in vivo FMO3 ontogeny is currently lacking. We derived in vivo FMO3 ontogeny by mechanistic population PK modelling of risdiplam and investigated its impact on drug-drug interactions in children.

Methods: Population 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:fm= 10%:90%, 50%:50%, 90%:10%).

Results: All 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.

Conclusion: Mech-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.