Olaparib is an inhibitor of poly (ADP-Ribose) polymerase (PARP) Enzymes: A Review

 

Mr. Mayur S. Jain*, Dr. Shashikant D. Barhate, Mr. Bhushan P. Gayakwad, Mr. Prafull P. Patil

Shree. Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jammer, Maharashtra (India).

 

ABSTRACT:

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death^(1,2)

 

 

 

INTRODUCTION:

Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved targeted therapy for cancer, developed by scientists at the University of Sheffield, KuDOS Pharmaceuticals and later by AstraZeneca. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.^[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.^[2] In December 2014, olaparib was approved for use as a single agent by the EMA and the FDA.^[3][4][5] The FDA approval is for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.^[4] In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer. ^(1,2)

 

 

Olaparib is available as oral tablets marketed under the brand name Lynparza and was initially indicated as a maintenance therapy or monotherapy for the treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. On January 12, 2018, FDA expanded the approved use of Lynparza to include chemotherapy-experienced patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In a randomized clinical trial involving patients with HER2-negative metastatic breast cancer with a germline BRCA mutation, the median progression-free survival for patients taking Lynparza was 7 months compared to 4.2 months for patients taking chemotherapy only. Patient selection for this newly-approved indication can be performed based on an FDA-approved genetic test, called the BRAC Analysis CDx. ^(1,2)

 

 

 

 

Structure:

 

 

Chemical formula:

C₂₄H₂₃FN₄O₃

 

Molecular weight:

435.08 g/mol

 

Protein binding:

Approximately 82%

 

Volume of distribution:

167 +/-196 L following a single dose of 400mg olaparib.

 

IUPAC Name:

4-(3-{[4-(cyclopropylcarbonyl) piperazin-1-yl]carbonyl}-4-fluorobenzyl) phthalazin-1(2H)-one

 

Metabolism: 

Primarily CYP3A4 in vitro.

 

PHARMACOLOGY:

Indication:

indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy Indicated for the treatment of patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, who have been previously treated with chemotherapy.. ^(1,2,3)

 

Mechanism of action:

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death. ^(1,2,3)

 

Route of elimination:

44% via the urine and 42% via the feces.

 

Half life (t_50%):

11.9 hours, standard deviation 4.8 hours

 

Drug Interactions:

Acetyldigitoxin may decrease the cardiotoxic activities of Olaparib. Acetyldigoxin may decrease the cardiotoxic activities of Olaparib. Bevacizumab may increase the cardiotoxic activities of Olaparib. Cyclophosphamide may increase the cardiotoxic activities of Olaparib.

 

Medicinal uses:

·        Advanced ovarian cancer (with deleterious germline BRCA mutated (gBRCAm) as detected by an FDA-approved test) who have been treated with three or more prior lines of chemotherapy.

·        HER2-negative metastatic breast cancer (with deleterious or suspected gBRCAm), who have been treated with chemotherapy.

 

Toxicity:

The most commonly reported side effects reported during clinical trials included cough, constipation, dysguesia, peripheral deem, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in 2% of patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers. The majority of cases were fatal and the duration of therapy with olaparib in patients who developed secondary cancers varied from <6 months to >2 years. Complete blood count should be tested at baseline and monthly following therapy initiation to monitor for MDS/AML. Pneumonitis, including fatal cases, occurred in <1% of patients treated with olaparib. Patients should be monitored for new or worsening respiratory symptoms such as dyspnea, fever, cough, or wheezing. Olaparib was found to be teratogenic and causes embryo-fetal toxicity in rats. It should therefore be avoided during pregnancy and its use should be a combined with an effective contraception during treatment. ^(1,2,3)

 

CONCLUSION:

In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

 

 

Olaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment

 

ACKNOWLEDGEMENT:

The authors would like to thanks Shree. Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jamner Maharashtra (India) for supporting the fulfillment of this work.

 

CONFLICT OF INTEREST:

Declared none.

 

REFERENCES:

1.       Www.drugbank.com

2.       "Olaparib, a PARP Inhibitor". Health and Life.

3.       Frampton JE: Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. BioDrugs. 2015 Apr; 29(2):143-50. doi: 10.1007/s40259-015-0125-6. [PubMerd:25899311]

4.       Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM: 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. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. [PrubMed:18800822]

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Received on 08.04.2018       Accepted on 26.05.2018

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