Lynparza 150mg tablets

Indications

• Ovarian cancer (specialist use only)
• Fallopian tube cancer (specialist use only)
• Peritoneal cancer (specialist use only)
• Breast cancer (specialist use only)
• Adenocarcinoma of the pancreas (specialist use only)
• Prostate cancer (specialist use only)

Dosage

Adults: 300 mg

Mechanism of action

Olaparib selectively inhibits PARP1 and PARP2 enzymes, which are critical for the repair of single-strand breaks in DNA through the base excision repair pathway. By inhibiting PARP, olaparib leads to the accumulation of unrepaired single-strand breaks, resulting in double-strand breaks. In cells with BRCA mutations, which are deficient in homologous recombination repair, this accumulation results in genomic instability and cell death, a process referred to as synthetic lethality.

Pharmacodynamics

Olaparib exhibits cytotoxic effects against tumor cell lines, particularly those with deficiencies in DNA repair mechanisms such as BRCA1/2. It has demonstrated efficacy in reducing tumor growth in various preclinical models, both as a standalone treatment and in combination with other chemotherapeutic agents. Additionally, olaparib has been shown to enhance the effectiveness of DNA-damaging chemotherapy and radiotherapy, thereby acting as a chemosensitizer and radiosensitizer.

Pharmacokinetics

Olaparib is absorbed orally and has a bioavailability that is affected by food intake. Its pharmacokinetic profile shows distribution across tissues, with metabolism primarily occurring in the liver through CYP3A4. The drug's elimination half-life allows for twice-daily dosing, and it is primarily excreted through urine and feces. Dose adjustments may be necessary in cases of hepatic or renal impairment, and monitoring of blood counts is recommended during treatment.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment

Adverse effects

• Angioedema
• Haematological toxicity
• Pneumonitis
• Dizziness
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Anemia

Interactions

• Antifungals (azoles) - Severe (increases exposure)
• Grapefruit juice - Severe (increases exposure)
• St John's wort - Severe (decreases exposure)
• Aliskiren - Unknown (increases exposure)
• Dronedarone - Unknown (increases exposure)
• Fexofenadine - Unknown (increases exposure)
• Cobicistat - Unknown (increases exposure)
• Colchicine - Unknown (increases exposure)
• Combined hormonal contraceptives - Unknown (affects efficacy)
• Crizotinib - Unknown (increases exposure)

Precautions

• Monitor full blood count before treatment initiation, then monthly for the first 12 months and periodically thereafter
• Counsel patients about the effects on driving and skilled tasks due to risk of malaise and dizziness

Pregnancy

Manufacturer advises avoiding use due to toxicity in animal studies.

Breast-feeding

Manufacturer advises avoiding use during treatment and for 1 month after the last dose; no information available.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets
• Capsules

Mechanism of action

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.

Pharmacodynamics

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.