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General Description:

Risdiplam, identified by CAS number 1825352-65-5, is a notable compound with significant therapeutic applications. 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 , the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy , 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:

This drug is primarily indicated for: Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Risdiplam undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Risdiplam are crucial for its therapeutic efficacy: The T_max 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Risdiplam is an important consideration for its dosing schedule: The terminal elimination half-life of risdiplam is approximately 50 hours in healthy adults. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Risdiplam exhibits a strong affinity for binding with plasma proteins: Risdiplam is approximately 89% protein-bound in plasma, primarily to serum albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Risdiplam from the body primarily occurs through: Following the oral administration of 18mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine. Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Risdiplam is distributed throughout the body with a volume of distribution of: Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues. The apparent volume of distribution at steady-state is 6.3 L/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Risdiplam is a critical factor in determining its safe and effective dosage: For a 14.9kg patient, the apparent clearance of risdiplam is 6.3 L/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Risdiplam exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Risdiplam functions by: Spinal muscular atrophy (SMA) is a severe and progressive congenital neuromuscular disease resulting from mutations in the survival of motor neuron 1 (_SMN1_) gene responsible for making SMN proteins. Clinical features of SMA include degeneration of motor neurons in the spinal cord which ultimately leads to muscular atrophy and, in some cases, loss of physical strength. SMN proteins are expressed ubiquitously throughout the body and are thought to hold diverse intracellular roles in DNA repair, cell signaling, endocytosis, and autophagy. A secondary _SMN_ gene (_SMN2_) can also produce SMN proteins, but a small nucleotide substitution in its sequence results in the exclusion of exon 7 during splicing in approximately 85% of the transcripts - this means that only ~15% of the SMN proteins produced by _SMN2_ are functional, which is insufficient to compensate for the deficits caused by _SMN1_ mutations. Emerging evidence suggests that many cells and tissues are selectively vulnerable to reduced SMN concentrations, making this protein a desirable target in the treatment of SMA. Risdiplam is an mRNA splicing modifier for _SMN2_ that increases the inclusion of exon 7 during splicing, which ultimately increases the amount of functional SMN protein produced by _SMN2_. It does so by binding to two sites in _SMN2_ pre-mRNA: the 5' splice site (5'ss) of intron 7 and the exonic splicing enhancer 2 (ESE2) of exon 7. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Risdiplam is categorized under the following therapeutic classes: BCRP/ABCG2 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A7 Substrates, Cytochrome P-450 Substrates, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, Musculo-Skeletal System, Other Miscellaneous Therapeutic Agents, P-glycoprotein substrates, Peripheral Nervous System Agents, Survival Motor Neuron-2-directed RNA Interaction. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.