NIRAPARIX CAPSULE

Indications

• Advanced ovarian cancer (initiated by a specialist)

Mechanism of action

Niraparib selectively inhibits PARP-1 and PARP-2, which are vital for repairing single-strand breaks (SSBs) in DNA. Inhibition of these enzymes leads to the accumulation of SSBs, which can progress to double-strand breaks (DSBs) if not properly repaired. Tumor cells with homologous recombination deficiencies, such as those with mutations in BRCA1 or BRCA2, become reliant on PARP for repair. When PARP is inhibited, these cells cannot repair their DNA, resulting in increased genetic instability and cell death, a phenomenon referred to as 'synthetic lethality.' Niraparib's selectivity for PARP enzymes is approximately 100-fold higher than for other PARP family members.

Pharmacodynamics

Niraparib demonstrates cytotoxic effects in tumor cell lines, irrespective of BRCA1/2 status, suggesting its efficacy in a broader range of cancers with DNA repair deficiencies. Preclinical models have shown a reduction in tumor growth in both BRCA-deficient and proficient cancer models. Furthermore, niraparib may inhibit key neurotransmitter transporters, potentially contributing to off-target cardiovascular effects such as increased heart rate and blood pressure.

Pharmacokinetics

Niraparib is administered orally and is absorbed with a bioavailability that can be influenced by food intake. The drug is metabolized primarily via hepatic pathways, with both renal and hepatic impairments necessitating caution in dosing. Niraparib exhibits extensive distribution and has a half-life conducive to once-daily dosing. Its pharmacokinetics may be altered in patients with significant hepatic or renal impairment, and regular monitoring of blood counts and blood pressure is recommended during treatment.

Contra-indications

• Hypersensitivity to niraparib or any of its components
• Severe thrombocytopenia (platelet count below 150x10^9/litre)
• Pregnancy

Adverse effects

• Oedema
• Photosensitivity reactions
• Skin reactions
• Confusion
• Pneumonitis
• Thrombocytopenia
• Pancytopenia
• Posterior reversible encephalopathy syndrome (PRES)
• Hypertension

Interactions

• Caution with other medications that affect blood pressure
• Potential interactions with drugs that affect the metabolism of niraparib

Precautions

• Monitor full blood count weekly for the first month, then monthly for the next 10 months
• Monitor blood pressure weekly for the first 2 months, then monthly for the first year
• Caution in patients with severe hepatic impairment
• Caution in patients with severe renal impairment
• Control pre-existing hypertension before starting treatment

Pregnancy

Manufacturer advises avoidance due to limited information available.

Breast-feeding

Manufacturer advises avoidance during treatment and for 1 month after the last dose; no information available.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets of niraparib, available in 100 mg and 200 mg strengths

Mechanism of action

Niraparib is a potent and selective inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2. PARPs play an important role in DNA repair. They recognize and repair cellular DNA damage, such as single-strand breaks (SSBs) and double-strand breaks (DSBs). Different DNA repair pathways exist to repair these DNA damages, including the base excision repair (BER) pathway for SSBs and BRCA-dependent homologous recombination for DSBs. If BER is impaired, SSBs accumulate and become DSBs, forcing cells to rely on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining, to repair DNA damages. However, some cells can have defective or deficient HR resulting from specific mutations in DNA repair genes, such as BRCA1 and 2. Inhibiting PARPs in the presence of HR deficiency leads to a phenomenon called 'synthetic lethality,' whereby the PARP inhibitor impedes BER, leading to genetic instability and cell death. Selectivity towards PARP-1 and PARP-2 is 100-fold higher than for other PARP family members. Niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death.

Pharmacodynamics

Niraparib mediated cytotoxic effects in tumour cell lines with or without deficiencies in _BRCA1/2_. Decreased tumour growth was observed in both mouse xenograft models of human cancer cell lines with deficiencies in _BRCA1/2_ and human patient-derived xenograft tumour models with homologous recombination deficiency (HRD) that had either mutated or wild-type _BRCA1/2_. _In vitro_ studies suggest that niraparib inhibits dopamine, norepinephrine, and serotonin transporters, which may explain its off-target cardiovascular effects such as increased pulse rate and blood pressure.