Risdiplam

Absorption

The Tmax following oral administration is approximately 1-4 hours. Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days. The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.

Toxicity

Data regarding overdose of risdiplam are unavailable. Symptoms of overdose are likely to be consistent with risdiplam's adverse effect profile, and may therefore involve significant fever, diarrhea, and skin reactions.

Description

Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier.

The Uses of Risdiplam

Risdiplam is used in preparation of Imidazopyridazinyl Pyridopyrimidinones for treating spinal muscular atrophy. Gene splicing modulator.

Background

Risdiplam is an orally bioavailable mRNA splicing modifier used for the treatment of spinal muscular atrophy (SMA). It increases systemic SMN protein concentrations by improving the efficiency of SMN2 gene transcription. This mechanism of action is similar to its predecessor nusinersen, the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy onasemnogene abeparvovec, whereas risdiplam offers the ease of oral bioavailability.
Risdiplam was approved by the FDA in August 2020 for the treatment of spinal muscular atrophy (SMA). Set to be substantially cheaper than other available SMA therapies, risdiplam appears to provide a novel and relatively accessible treatment option for patients with SMA regardless of severity or type.

Indications

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA).

Pharmacokinetics

Risdiplam helps to alleviate symptoms of spinal muscular atrophy by stimulating the production of a critical protein in which these patients are deficient. Early trials with risdiplam demonstrated up to a 2-fold increase in SMN protein concentration in SMA patients after 12 weeks of therapy.

Metabolism

The metabolism of risdiplam is mediated primarily by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7. Parent drug comprises approximately 83% of circulating drug material.
A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite - this M1 metabolite has been observed in vitro to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.