417 Human biotransformation of olaparib (AZD2281) an oral poly(ADP-ribose) polymerase (PARP) inhibitor

Clarkson-Jones, J.; Page, Curtis P.; Puig, Susana; Swaisland, Helen

doi:10.1016/s1359-6349(10)72124-8

Cited by 3 publications

(2 citation statements)

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“…Olaparib is primarily excreted unchanged in the urine and consequently, olaparib's renal clearance is decreased in patients with diminished renal function [141]. Furthermore, in patients with mild (GFR = 51-80 mL/min) to moderate renal impairment (GFR = 31-50 ml/min), there was a decrease in the volume of distribution and terminal half-life compared to patients with normal renal function [145,146]. The most common adverse events of any grade reported following treatment with olaparib were nausea, fatigue, vomiting, anemia and diarrhea, although severe grade 3 or 4 anemias have been reported in some patients and this could be managed by a dose reduction [147,148].…”

Section: Olaparibmentioning

confidence: 99%

Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers

Silpa¹,

Teng²,

Jagadish³

et al. 2019

J. Mol. Clin. Med.

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Poly (ADP-ribose) polymerase (PARP) proteins mediate various cellular processes such as DNA repair, regulation of transcription, protein-protein interaction, expression of inflammatory genes and programmed cell death. PARP proteins have a key role in DNA repair and recent findings have established the role of PARP inhibitors as potent chemotherapeutic drugs. Among the 18 members, PARP1 and PARP2 have been identified as the main targets for the development of pharmacological inhibitors to enhance the cytotoxic efficacy of established anticancer drugs. Furthermore, certain PARP1 and PARP2 inhibitors are being used in combination with other drugs for the treatment of various types of cancer. In different drug resistant cancer cell types, PARP inhibitors have been identified as compounds that reverse the resistance to topoisomerase inhibitors, DNA alkylating and methylating drugs by enhancing the DNA damage induced by these agents. In BRCA mutant cells, with abnormal homologous recombination (HR) repair mechanism, BER (Base Excision Repair Pathway) is responsible for survival of the cells. PARP enzymes play a major role in BER and PARP inhibitors effectively target BRCA mutant cells sparing normal cells via the concept of synthetic lethality, producing minimal toxicity to PARP inhibitors also have a significant role in treating pancreatic adenocarcinoma and castration-resistant prostate cancer. The aim of the current paper is to provide a review on PARP inhibitors and their application in the treatment of various cancer cells which are resistant to standard chemotherapeutic drugs.

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Section: Olaparibmentioning

confidence: 99%

Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers

Silpa¹,

Teng²,

Jagadish³

et al. 2019

J. Mol. Clin. Med.

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“…The peak plasma concentration is reached at 1-3 h after oral intake of olaparib, followed by a biphasic decline in plasma concentrations, with a terminal elimination halflife (t ) of 5-7 h [50]. The main metabolism of olaparib occurs via dehydrogenation and oxidation, with a number of components that were further metabolized by glucuronide or sulphate conjugation [52]. Ang et al performed a mass balance study of olaparib and found that excretion of the drug occurs mostly via feces (42%) and urine (44%) [53] (Table 1).…”

Section: Olaparibmentioning

confidence: 99%

PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer

et al. 2017

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Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis. It has a high prevalence of BRCA1 mutations and an increased Ki-67 expression. This subtype usually responds well to taxanes and/or platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. Studies with PARP inhibitors have demonstrated promising results in the treatment of BRCA-mutated breast and ovarian cancer, and PARP inhibitors have been studied as monotherapy and in combination with cytotoxic therapy or radiotherapy. PARP inhibitor efficacy on poly (ADP-ribose) polymer (PAR) formation in vivo can be quantified by pharmacodynamic assays that measure PAR activity in peripheral blood mononuclear cells (PBMC). Biomarkers such as TP53, ATM, PALB2 and RAD51C might be prognostic or predictive indicators for treatment response, and could also provide targets for novel treatment strategies. In summary, this review provides an overview of the treatment options for basal-like TNBC, including PARP inhibitors, and focuses on the pharmacotherapeutic options in these patients.

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Olaparib: First Global Approval

Deeks

2015

Drugs

144

104

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Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer.

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417 Human biotransformation of olaparib (AZD2281) an oral poly(ADP-ribose) polymerase (PARP) inhibitor

Cited by 3 publications

References 0 publications

Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers

Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers

PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer

Olaparib: First Global Approval

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