Olaparib

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Signal Transduction Inhibitors; PARP inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H301 (92.5%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P264, P270, P273, P280, P301+P316, P318, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 40 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In pre-registration clinical trials of olaparib, abnormalities in routine liver tests were uncommon with serum aminotransferase elevations occurring in 4% of patients and values above 5 times the upper limit of normal (ULN) in 1% or less. In early trials of olaparib in patients with various advanced solid tumors there were no reports of hepatitis with jaundice or liver failure. However, after its approval and more widescale use, there have been several published reports of clinically apparent liver injury attributed to olaparib, some of which have been severe and some fatal. The onset of injury arose after 2 to 3 months of therapy and was typically hepatocellular with marked elevations in serum ALT and AST but only modest elevations in alkaline phosphatase levels. Rash and fever were uncommon, but low titers of ANA and SMA were reported, and clinical features as well as a rapid response to corticosteroid therapy were typical. Liver biopsies demonstrated hepatocellular injury with variable amounts of lobular necrosis and intense portal infiltration with lymphocytes and eosinophils with rare plasma cells. Thus, olaparib appears to be a definite cause of idiosyncratic liver injury and regular monitoring of liver tests is now recommended.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Olaparib is a cytotoxic and anti-tumour agent. Olaparib inhibits the growth of selective tumour cell lines _in vitro_ and decreases tumour growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. The drug exerts anti-tumour effects in cell lines and mouse tumour models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In preclinical models of cancer, olaparib demonstrated anti-tumour activity when used alone, in combination with chemotherapeutic agents, or radiotherapy. Olaparib can act as a chemosensitizer to potentiate the cytotoxicity of DNA-damaging chemotherapeutic agents such as alkylating agents and platinum-based drugs. It can also act as a radiosensitizer by preventing PARP-mediated DNA repair.

Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes comprising 17 members. They are involved in essential cellular functions, such as DNA transcription and DNA repair. PARPs 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. Olaparib is a PARP inhibitor: while it acts on PARP1, PARP2, and PARP3, olaparib is a more selective competitive inhibitor of NAD⁺ at the catalytic site of PARP1 and PARP2. Inhibition of the BER pathway by olaparib leads to the accumulation of unrepaired SSBs, which leads to the formation of DSBs, which is the most toxic form of DNA damage. While BRCA-dependent homologous recombination can repair DSBs in normal cells, this repair pathway is defective in cells with BRCA1/2 mutations, such as certain tumour cells. Inhibition of PARP in cancer cells with BRCA mutations leads to genomic instability and apoptotic cell death. This end result is also referred to as synthetic lethality, a phenomenon where the combination of two defects - inhibition of PARP activity and loss of DSB repair by HR - that are otherwise benign when alone, lead to detrimental results. _In vitro_ studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.