Risdiplam exhibits time-dependent inhibition of CYP3A in vitro so drug-drug interactions (DDI) were a concern. But, conducting a clinical study in pediatric SMA patients was not feasible. A novel PBPK strategy involving the Simcyp Simulator, Certara’s physiologically based PBPK platform, was used to extrapolate the DDI risk from healthy adults to children with SMA. Model-based prediction of in vivo CYP3A inhibition of Risdiplam using PBPK models for healthy adults and patients with SMA, including pediatric populations, were conducted.

Validation of the risdiplam and midazolam PBPK model for healthy adults using the observations of the clinical DDI study followed, included refinement of the in vivo data, facilitating the extrapolation and DDI risk assessments using the pediatric risdiplam PBPK model. Different ontogeny functions of the CYP3A enzyme predicted different susceptibility to CYP3A modulations in children, and thus various functions were considered. The risdiplam PBPK model was validated with independent data for each population. The PBPK-predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months–18 years was negligible and included in the prescribing information.

Graphic 1

Pediatric PBPK modeling performed iteratively with well-designed clinical study in adults enables prospective DDI risk assessments in children.

Spinal muscular atrophy (SMA) is a rare genetic disease that progressively destroys motor neurons—nerve cells in the brain stem and spinal cord that control essential skeletal muscle activity such as speaking, walking, breathing, and swallowing, leading to muscle weakness and atrophy. It typically begins in infancy or childhood and affects about 1 in 11,000 babies.

Nervous System


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