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General Description:

Palovarotene, identified by CAS number 410528-02-8, is a notable compound with significant therapeutic applications. Fibrodysplasia Ossificans Progressiva (FOP), with an estimated worldwide prevalence of one in 2 million individuals, is an exceptionally rare genetic disorder. FOP is caused by a gain-of-function mutation in the ACVR1/ALK2 gene which results in progressive heterotopic ossification, a process wherein connective tissues (e.g. skeletal muscle, ligaments, tendons) are replaced with bone. The ossification occurring as a result of FOP is insidious and cumulative, and is provoked during flare-ups or in response to injury. Treatment options for patients with FOP are extremely limited, although there has been substantial recent interest in novel treatments for this disease. Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ) belonging to a class of medications known as retinoids, similar in mechanism to drugs like or , which are derivatives of . It first garnered interest as a potential treatment for emphysema, but was eventually recognized as a potential novel therapy for patients with FOP. Agonists for retinoic acid receptors have been shown to inhibit chondrogenesis of heterotopic ossification in a transgenic mice model of FOP, with selective RARγ agonists (e.g. palovarotene) demonstrating the greatest efficacy. Palovarotene was approved for use in Canada in January 2022 for the management of heterotopic ossification in patients with FOP, representing the first global approval for any FOP therapy. It has been granted rare pediatric disease and breakthrough therapy designations from the US FDA, although a previously submitted NDA was withdrawn in August 2021 pending the resubmission of additional data analyses.

Indications:

This drug is primarily indicated for: Palovarotene is indicated in Canada to reduce the formation of heterotopic ossification in adults and children (≥8 years old for females and ≥10 years old for males) with Fibrodysplasia Ossificans Progressiva (FOP). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Palovarotene undergoes metabolic processing primarily in: Palovarotene undergoes extensive metabolism by CYP3A4 and, to a lesser extent, CYP2C8 and CYP2C19. Five metabolites have been observed in plasma: M1 (6,7-dihydroxy), M2 (6-hydroxy), M3 (7-hydroxy), M4a (6-oxo), and M4b (7-oxo). Following oral administration of palovarotene, the parent drug and its four main metabolites (M2, M3, M4a, and M4b) account for approximately 40% of total plasma exposure. The metabolites of palovarotene are functionally inactive, with M3 and M4b carrying 1.7% and 4.2% of the activity of their parent compound, respectively. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Palovarotene are crucial for its therapeutic efficacy: Following oral administration of 20mg once daily in healthy adult subjects, the median T_max was 4.6 hours, the mean C_max was 140 ng/mL, and the mean AUC_(0-τ) was 942 ng*hr/mL. At steady-state, the mean trough concentration of palovarotene was 3.5 ng/mL. The administration of palovarotene with a high-fat, high-calorie meal resulted in an approximate 40% increase in AUC, an approximate 16% increase in C_max, and a delay in T_max by approximately 2 hours when compared to its administration under fasting conditions. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Palovarotene is an important consideration for its dosing schedule: The mean elimination half-life of palovarotene at steady-state is 8.7 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Palovarotene exhibits a strong affinity for binding with plasma proteins: Palovarotene is 99% protein-bound _in vitro_, although the specific proteins to which it binds are unclear. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Palovarotene from the body primarily occurs through: Following the administration of a 1mg radiolabeled dose of palovarotene in healthy subjects, approximately 97.1% of the administered radioactivity was recovered in the feces, with only 3.2% recovered in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Palovarotene is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution of palovarotene at steady-state is 319 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Palovarotene is a critical factor in determining its safe and effective dosage: The apparent total body clearance of palovarotene is approximately 19.9 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Palovarotene exerts its therapeutic effects through: Palovarotene exerts its pharmacologic effects by inhibiting the pathway(s) responsible for heterotopic ossification in patients with FOP. It is orally bioavailable and can be administered once daily, with allowances for short-term increases in dosage in the event of a flare-up. As with other retinoids, palovarotene can cause birth defects, and it should not be used by patients who are, or intend to become, pregnant. Palovarotene is contraindicated in patients of childbearing potential unless a number of pregnancy prevention strategies are met (e.g. effective contraception, regular pregnancy testing). Palovarotene may also cause a premature physeal closure in growing children. Physeal growth plates should be monitored every 3 months throughout therapy, or more frequently if evidence of adverse effects on growth are observed. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Palovarotene functions by: The pathogenesis of FOP is driven by a gain-of-function mutation in the _ACVR1/ALK2_ gene encoding activin A receptor type 1 (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein type 1 receptor (BMPR-I). BMP signaling begins with the complexation of BMPR-II and BMPR-I, which initiates an intracellular signaling pathway mediated by phosphorylated SMAD proteins. The sustained and aberrant signaling caused by the gain-of-function mutation in _ACVR1/ALK2_ results in an overactivation of the downstream SMAD1/5/8 signaling pathway, which in turn is thought to trigger the formation of ectopic chondrogenesis, osteogenesis, and joint fusion characteristic of FOP. Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ), a receptor expressed in chondrogenic cells and chondrocytes that acts as a transcriptional repressor. In binding to RARγ, palovarotene decreases BMP signaling and subsequently inhibits the SMAD1/5/8 signaling pathway. Palovarotene's interference with these pathways inhibits chondrogenesis and allows for normal muscle tissue repair to take place, ultimately reducing damage to muscle tissue. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Palovarotene belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids, classified under the direct parent group Stilbenes. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Stilbenes class, specifically within the None subclass.

Categories:

Palovarotene is categorized under the following therapeutic classes: Benzene Derivatives, Benzylidene Compounds, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Musculo-Skeletal System, Retinoids. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Palovarotene include:

• Water Solubility: 0.04 μg/mL