Olaparib

Absorption

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.

Toxicity

The oral LD50 in rats is approximately 240-300 mg/kg.
There is limited information regarding the overdose of olaparib.

Description

Olaparib, marketed by AstraZeneca under the brand name Lynparza , was approved in the USA in December 2014 as a targeted, single-agent therapy for the treatment of germline BRCA-mediated advanced ovarian cancer.Olaparib, originally developed by KuDOS pharmaceuticals and later by AstraZeneca, functions as a poly ADP ribose polymerase inhibitor and has been specifically approved for patients who have received three or more treatments of chemotherapy. In clinical trials, the drug prolonged progression- free survival for patients suffering from platinum-sensitive recurrent serous ovarian cancer. Olaparib is also currently in various phases of investigation for treatment of breast, gastric, prostate, pancreatic and non-small cell lung cancer.

Chemical properties

White Solid

The Uses of Olaparib

Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor. Olaparib has been shown to induce significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Recent studies show that Olaparib increases radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy.

What are the applications of Application

Olaparib is a potent inhibitor of both PARP-1 and PARP-2 and is strongly sensitive to KB2P cells due to suppression of base excision repair by PARP inhibition

Background

Olaparib is a selective and potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2. PARP inhibitors represent a novel class of anti-cancer therapy and they work by taking advantage of a defect in DNA repair in cancer cells with BRCA mutations and inducing cell death.
Olaparib is used to treat a number of BRCA-associated tumours, including ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. It was first approved by the FDA and EU in December 2014, and by Health Canada in April 2016.

Indications

Ovarian cancer
Olaparib is indicated for the maintenance treatment of adults with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.
Olaparib is indicated in combination with bevacizumab for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.
Olaparib 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.
Breast cancer
Olaparib is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.
Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR) positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.
Pancreatic cancer
Olaparib is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.
Prostate cancer
Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with a hormone agent, such as enzalutamide or abiraterone.
It is also indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

Definition

ChEBI: Olaparib is a member of the class of N-acylpiperazines obtained by formal condensation of the carboxy group of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid with the free amino group of N-(cyclpropylcarbonyl)piperazine; used to treat advanced ovarian cancer. It has a role as an antineoplastic agent, an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor and an apoptosis inducer. It is a N-acylpiperazine, a member of cyclopropanes, a member of monofluorobenzenes and a member of phthalazines.

Biological Activity

Many of the products generated by alkylating agents on DNA can be efficiently repaired by normal base excision repair (BER). Some poly(ADP-ribose) polymerases (PARPs) assist in the repair of single-strand DNA nicks, an important step in BER. Olaparib is a potent inhibitor of PARP1 and PARP2 (IC50 = 5 and 1 nM, respectively) but is less effective against the PARP tankyrase-1 (IC50 = 1.5 μM). It can be used in cells and in animals, alone or in combination therapy with alkylating agents, to block BER and increase cancer cell death.[Cayman Chemical]

Pharmacokinetics

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.

Clinical Use

Human poly (ADP-ribose) polymerase enzymes inhibitor:
Treatment of platinum-sensitive relapsed BRCAmutated high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer

Synthesis

This optimized synthesis begins with reaction of commercially available dimethyl phosphite and 2-carboxybenzaldehyde (201) to generate the corresponding phosphonate ester in 95% yield and 95% purity after aqueous workup.190 Addition of aldehyde 202 to this phosphonate ester intermediate in the presence of triethylamine led to formation of olefins 203a/203b in 96% yield as a 1:1 mixture of E/Z isomers. From olefins 203a/203b, a one-pot, three-step sequence was next performed to provide access to dihydrophthalazinyl acid 204. First, lactone ring-opening and nitrile hydrolysis was facilitated by reaction with aqueous sodium hydroxide under elevated temperatures, allowing for subsequent in situ formation of the corresponding dihydrophthalazine intermediate after addition of hydrazine hydrate. Acidification and precipitation of product with 2 N HCl led to isolation of the desired material in 77% yield and 96% purity after filtration. Further coupling of carboxylic acid 204 with Bocpiperazine (205) (HBTU, DIPEA, DMA) and subsequent removal of the carbamate with HCl/EtOH provided intermediate 206 in 46% yield from 204, relying on a pH-controlled workup procedure to enable isolation of material in high purity (94%) without requiring chromatography. The final step of the olaparib synthesis was completed via treatment of piperazine 206 with cyclopropane carbonyl chloride (207) and triethylamine, leading to isolation of olaparib in 90% yield and 99.3% purity after distillation.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - avoid or reduce olaparib dose to 150 mg twice daily; avoid with rifabutin and rifampicin.
Antidepressants: avoid with St John’s wort.
Antiepileptics: avoid with carbamazepine, phenobarbital and phenytoin.
Antifungals: concentration increased by itraconazole and possibly fluconazole - avoid or reduce olaparib dose to 150 mg twice daily.
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.
Antivirals: concentration possibly increased by boceprevir, ritonavir and telaprevir - avoid or reduce olaparib dose to 150 mg twice daily; avoid with nevirapine.
Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - avoid or reduce olaparib dose to 150 mg twice daily.
Cobicistat: concentration possibly increased - avoid or reduce olaparib dose to 150 mg twice daily.
Grapefruit juice: avoid concomitant use.
Oestrogens and progestogens: possibly reduced contraceptive effect.

Metabolism

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.

Metabolism

In vitro, CYP3A4 was shown to be the main enzyme responsible for the metabolism of olaparib. The majority of the metabolism was due to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
Following a single dose of [14C]-olaparib, approximately 86% of the dose was recovered within a 7-day collection period, approximately 44% via the urine and 42% via the faeces. The majority of olaparib was excreted as metabolites.

storage

Store at -20°C

Mode of action

Olaparib is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.

References

1) Menear?et al. (2008),?4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose)polymerase-1;? J. Med. Chem.,?51?6581
2) Rottenberg?et al. (2008),?High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs; Proc. Natl. Acad. Sci. USA,?105?17079
3) Avila-Arroyo?et al. (2015),?Synergistic effect of Trabectedin and Olaparib combination regimen in breast cancer cell lines; J. Breast Cancer,?18?329
4) Xu?et al. (2015),?Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer; Onco. Targets Ther.,?8?3047
5) Ghonim?et al. (2015),?PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice; Clin. Sci.(Lond),?129?951