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General Description:

Rucaparib, identified by CAS number 283173-50-2, is a notable compound with significant therapeutic applications. Rucaparib is an anticancer drug and poly (ADP-ribose) polymerase (PARP) inhibitor. PARP is an enzyme that plays an essential role in DNA repair. Rucaparib is proposed to work in several PARP-dependent and PARP-independent mechanisms of action; however, it causes a unique effect of synthetic lethality. By targeting the genetically-mutated cancer cells that lack a DNA repair mechanism, rucaparib causes cancer cell death and reduces tumour growth. Rucaparib was granted FDA Breakthrough Therapy designation in April 2015 and accelerated approval in December 2016. The drug was later approved by the European Commission in May 2018. It is currently used to treat recurrent ovarian and prostate cancer in adults.

Indications:

This drug is primarily indicated for: Rucaparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Under accelerated approval by the FDA, rucaparib is also indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Rucaparib undergoes metabolic processing primarily in: In vitro, rucaparib is primarily metabolized by CYP2D6 and, to a lesser extent, by CYP1A2 and CYP3A4. In addition to CYP-based oxidation, rucaparib also undergoes N-demethylation, N-methylation, and glucuronidation. In one study, seven metabolites of rucaparib were identified in plasma, urine, and feces. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Rucaparib are crucial for its therapeutic efficacy: Rucaparib exhibits a linear pharmacokinetic profile over the dose range from 240 mg to 840 mg twice daily. The mean (coefficient of variation ) steady-state rucaparib C_max is 1940 ng/mL (54%) and AUC0-12h is 16900 h x ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold. The median T_max at the steady state is 1.9 hours, with a range of 0 to 5.98 hours at the approved recommended dosage. The mean absolute bioavailability is 36%, with a range of 30 to 45%. A high-fat meal increased C_max and AUC_0-24h by 20% and 38%, respectively. The T_max was delayed by 2.5 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Rucaparib is an important consideration for its dosing schedule: The mean (coefficient of variation) terminal elimination half-life is 26 (39%) hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Rucaparib exhibits a strong affinity for binding with plasma proteins: Rucaparib is 70% bound to human plasma proteins _in vitro_. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.8. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Rucaparib from the body primarily occurs through: Following a single oral dose of radiolabeled rucaparib, unchanged rucaparib accounted for 64% of the radioactivity. Rucaparib accounted for 45% and 95% of radioactivity in urine and feces, respectively. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Rucaparib is distributed throughout the body with a volume of distribution of: The mean (coefficient of variation) apparent volume of distribution is 2300 L (21%). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Rucaparib is a critical factor in determining its safe and effective dosage: The mean (coefficient of variation) apparent total clearance at steady state is 44.2 L/h (45%). It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Rucaparib exerts its therapeutic effects through: Rucaparib is an anticancer agent that exerts cytotoxic effects against cancer cells. It works by inhibiting poly (ADP-ribose) polymerase (PARP), an enzyme that plays a role in DNA repair. Rucaparib inhibits PARP-1, PARP-2, and PARP-3. It also interacts with PARP-4, PARP-10, PARP-12, PARP-15, and PARP-16, but to a lesser extent. In mice, rucaparib accumulated and was retained in tumours, inhibiting PARP enzymes for seven days. Rucaparib decreases tumour growth in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. In addition to PARP inhibition, rucaparib demonstrated PARP-independent cytotoxic mechanisms in cancer cells. When co-administered with other chemotherapeutic agents, rucaparib contributed to synergistic or additive effects _in vitro_ and _in vivo_. There is evidence that rucaparib can sensitize cancer cells to chemotherapy. Rucaparib can also cause vasodilation, which may increase tumour perfusion and enhance the accumulation of cytotoxic drugs in cancer cells. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Rucaparib functions by: PARPs play a role in DNA repair by activating DNA damage response pathways, such as base excision repair, and facilitating DNA repair. PARPs were evaluated as novel anticancer therapeutic targets after discovering that PARP-1 inhibitors reduce tumour growth in BRCA-deficient cancers. BRCA1 and BRCA2 are tumour suppressor genes involved in various cellular processes related to cell growth and death, including DNA repair. More specifically, BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair. Cancer cells with a deleterious BRCA mutation are HR-deficient, resulting in unregulated and aberrant cell repair and growth. Rucaparib inhibits PARP1, PARP2, and PARP3. Inhibiting PARP traps the enzyme on damaged DNA, halting the repair process and forming toxic PARP–DNA complexes. Alternatively, other DNA repair processes such as error-prone nonhomologous end joining (NHEJ) or alternative end-joining pathways can be initiated, leading to mutations or chromosomal change. Further DNA damage can trigger cancer cell apoptosis and cell death. Typically, inhibition of PARP converts single-strand breaks in DNA to double-strand breaks at replication forks. HR DNA repair pathways repair double-strand breaks; however, HR-deficient cancer cells lack this repair mechanism. Because HR-deficient cancer cells are more vulnerable to unsalvageable DNA damage, rucaparib-induced PARP inhibition leads to synthetic lethality. In this phenomenon, two non-lethal defects (HR deficiency and PARP inhibition) combine and cause cell death. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Rucaparib belongs to the class of organic compounds known as 2-phenylindoles. These are indoles substituted at the 2-position with a phenyl group, classified under the direct parent group 2-phenylindoles. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Indoles and derivatives class, specifically within the Indoles subclass.

Categories:

Rucaparib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, BCRP/ABCG2 Substrates, Cytochrome P-450 CYP1A2 Inducers, Cytochrome P-450 CYP1A2 Inducers (moderate), Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (weak), Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP1A2 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (weak), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (moderate), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP2D6 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (weak), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (strength unknown), Cytochrome P-450 CYP3A7 Inhibitors, Cytochrome P-450 CYP3A7 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Enzyme Inhibitors, Heterocyclic Compounds, Fused-Ring, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, Narrow Therapeutic Index Drugs, OAT1/SLC22A6 inhibitors, OAT3/SLC22A8 Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, OCT1 inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, P-glycoprotein substrates with a Narrow Therapeutic Index, Poly (ADP-ribose) polymerase (PARP) inhibitors, Poly(ADP-ribose) Polymerase Inhibitors, UGT1A1 Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Rucaparib include:

• Water Solubility: 1 mg/mL