オラパリブ

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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Olaparib

vLess-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

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.

Olaparib is metabolized by cytochrome P450 (CYP) 3A4/5 _in vitro_. Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma. Olaparib undergoes oxidation reactions as well as subsequent glucuronide or sulfate conjugation. In humans, olaparib can also undergo hydrolysis, hydroxylation, and dehydrogenation. While up to 37 metabolites of olaparib were detected in plasma, urine, and feces, the majority of metabolites represent less than 1% of the total administered dose and they have not been fully characterized. The major circulating metabolites are a ring-opened piperazin-3-ol moiety and two mono-oxygenated metabolites. The pharmacodynamic activity of the metabolites is unknown.

WOH1JD9AR8

OLAPARIB

Established Pharmacologic Class [EPC] - Poly(ADP-Ribose) Polymerase Inhibitor

Mechanisms of Action [MoA] - Poly(ADP-Ribose) Polymerase Inhibitors

Olaparib is a Poly(ADP-Ribose) Polymerase Inhibitor. The mechanism of action of olaparib is as a Poly(ADP-Ribose) Polymerase Inhibitor.

OLAPARIB

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES.

Following oral administration, olaparib is rapidly absorbed. After administration of a single 300 mg dose of olaparib, the mean (CV%) Cmax was 5.4 μg/mL (32%) and AUC was 39.2 μg x h/mL (44%). The steady state Cmax and AUC following a dose of 300 mg twice daily was 7.6 μg/mL (35%) and 49.2 μg x h/mL (44%), respectively. Tmax is 1.5 hours. A high-fat and high-calorie meal may delay Tmax, but does not significantly alter the extent of olaparib absorption.

Following a single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within a seven-day collection period, mostly in the form of metabolites. About 44% of the drug was excreted via the urine and 42% of the dose was excreted via the feces. Following an oral dose of radiolabeled olaparib to female patients, the unchanged drug accounted for 15% and 6% of the radioactivity in urine and feces, respectively.

The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose.

Following a single oral dose in patients with cancer, the mean apparent plasma clearance was 4.55 L/h.