Niraparib

320.39

320.39

HMC2H89N35

DTXSID50146129

C80059

L01XK02|L - Antineoplastic and immunomodulating agents

72.9

2.2

463.619°C at 760 mmHg

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501|Aggregated GHS information provided by 36 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In preregistration, randomized controlled clinical trials of niraparib, abnormalities in routine liver tests were common, but were mostly mild and self-limited in course. Serum ALT elevations occurred in 28% of patients (vs 15% of controls), but values were above 5 times the upper limit of normal (ULN) in only 1% (vs 2% of controls). Despite the frequency of serum enzyme elevations during therapy in clinical trials, there were no reports of hepatitis with jaundice or liver failure. Subsequent to its approval and more wide scale use, there have been no published reports of clinically apparent liver injury attributed to niraparib, but the extent and duration of its use have been limited. Thus, niraparib is a known cause of mild serum enzyme elevations but has not been linked to significant hepatotoxicity.

Niraparib is 83.0% bound to human plasma proteins.

Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy|Zejula is indicated:as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.as monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum based chemotherapy.|Treatment of prostate malignant neoplasms|Drug: Niraparibtosylatemonohydrate

Niraparib is a small molecule inhibitor of poly ADP-ribose polymerase that is used in the therapy of selected patients with refractory and advanced ovarian carcinoma. Niraparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy, but has not been linked to instances of clinically apparent liver injury.

Antineoplastic Agents

Cardiovascular Effects: Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT). In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. Cardiac Electrophysiology The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily.

Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES. (See all compounds classified as Poly(ADP-ribose) Polymerase Inhibitors.)

The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib. Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg.|Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces.|The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L.|the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.

Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.

Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours.

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that 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. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

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