Niraparib


Niraparib is an orally active small molecule PARP inhibitor developed by Tesaro to treat ovarian cancer.
Niraparib was granted fast track designation by the US Food and Drug Administration, and Tesaro submitted a new drug application in 2016. It was approved on 27 March 2017 in the US, and has been approved in Europe on 16 November 2017.

Medical uses

The drug is approved by the US FDA 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.
In a study with 553 patients, progression-free survival for patients with a deleterious or suspected deleterious BRCA mutation in the germline was 21.0 months under niraparib therapy, as compared to 5.5 months under placebo. Patients without such a mutation had a PFS of 9.3 months under niraparib versus 3.9 months under placebo.

Contraindications

No contraindications are listed in the prescribing information.

Side effects

The most common side effects in studies were low blood cell counts, namely thrombocytopenia, anemia and neutropenia. Other, mostly mild to moderate side effects included nausea, fatigue, and constipation. In a study running over 250 days, 15% of patients had to permanently discontinue niraparib due to adverse effects.

Interactions

No clinical interaction studies have been performed. The potential for interactions with other drugs is low as niraparib and its main metabolite M1 do not significantly interact with any of the important cytochrome P450 liver enzymes in vitro. Niraparib, but not M1, is transported by P-glycoprotein and BCRP, but does not significantly inhibit them. Neither niraparib nor M1 significantly interact with any of the other important transporter proteins.

Pharmacology

Mechanism of action

Niraparib is an inhibitor of the enzymes PARP1 and PARP2.

Pharmacokinetics

73% of ingested niraparib is absorbed in the gut, and it reaches highest blood plasma concentrations after about three hours, independently of food intake. In the circulation, 83% of the substance are bound to plasma proteins. It is inactivated by carboxylesterases to the main metabolite M1, the carboxylic acid derivative, which is subsequently glucuronidated.
The mean biological half-life is 36 hours. 47.5% of the substance are found in the urine and 38.8% in the feces. Unmetabolised niraparib accounts for 11% in the urine and 19% in the feces.

Chemistry

The drug is used in form of the salt niraparib tosylate monohydrate, which is white to off-white, non-hygroscopic crystals.

Studies

A 2012 study in a cell line found that PARP inhibitors exhibit cytotoxic effects not based solely on their enzymatic inhibition of PARP, but by their trapping of PARP on damaged DNA, and the strength of this trapping activity was ordered niraparib >> olaparib >> veliparib.