Indications
Risdiplam is prescribed for the management of spinal muscular atrophy (SMA), a genetic condition characterized by progressive muscle weakness due to motor neuron loss. It addresses the underlying cause by increasing the levels of survival motor neuron (SMN) protein, which is deficient in patients suffering from this condition.
Pharmacodynamics
Risdiplam exerts its therapeutic effects by enhancing the production of the SMN protein, essential for motor neuron health and function. Clinical trials have demonstrated that treatment with risdiplam can lead to an approximate twofold increase in SMN protein concentrations in patients over a 12-week period, thereby helping to mitigate the symptoms associated with SMA.
Absorption
After oral administration, risdiplam is absorbed relatively quickly, with peak plasma concentrations (Tmax) occurring between 1 to 4 hours. When taken once daily alongside a morning meal or after breastfeeding, risdiplam achieves a steady state within 7 to 14 days. The pharmacokinetic profile of risdiplam is linear across the dosages studied in SMA patients.
Metabolism
The metabolic processing of risdiplam is primarily facilitated by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with additional contributions from cytochrome P450 enzymes CYP1A1, CYP2J2, CYP3A4, and CYP3A7. The unchanged parent compound constitutes roughly 83% of the circulating active substance. The main metabolite, M1, although pharmacologically inactive, is notable for its ability to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.
Mechanism of Action
Risdiplam functions as an mRNA splicing modifier specifically targeting the SMN2 gene to enhance the production of functional SMN protein. The mechanism of action involves increasing the inclusion of exon 7 during the SMN2 splicing process. This is achieved by the binding of Risdiplam to two critical sites on the SMN2 pre-mRNA: the 5' splice site of intron 7 and the exonic splicing enhancer 2 of exon 7. By promoting the full inclusion of exon 7, Risdiplam augments the synthesis of functional SMN protein, thereby addressing the deficit caused by mutations in the SMN1 gene. This targeted approach is designed to ameliorate the protein insufficiency observed in Spinal Muscular Atrophy, where reduced SMN concentrations render cells and tissues vulnerable, contributing to the disease's progression.
