Olaparib - Uses, Mechanism of Action, Side Effects, and Precautions

Overview:

Olaparib is a prescription-only medicine used to treat breast cancer susceptibility protein (BRCA) associated with advanced ovarian cancer in adults. Olaparib inhibits poly ADP ribose polymerase (PARP) enzymes. The function of the PARP enzyme is to repair the DNA. Thus Olaparib stops the repair of the single-stranded DNA damage by inhibiting the PARP enzyme. Olaparib is lethal to cancer cells inherited with BRCA1 or BRCA2 mutations. These mutations are mainly involved in causing ovarian, breast, and prostate cancers.

Olaparib as a single agent was approved against these cancers by the food and drug administration (FDA) in December 2014. Olaparib is commercially available as LYNPARZA in the following forms and strengths.

• 100 mg - yellow in color. The shape is oval and biconvex. The layer is film-coated with debossed characters OP100 on one side and plain on the other.

• 150 mg - in green or green-gray color. The shape is oval and biconvex. The layer is film-coated with debossed characters OP150 on one side and plain on the other.

How Does Olaparib Work?

Olaparib is a poly ADP ribose polymerase (PARP) inhibitor. It works by inhibiting the enzymatic action of PARP.

BRCA1 or BRCA2 mutated persons are at risk of developing some kinds of cancer that are different from the other cancer forms and do not respond to usual cancer treatment strategies. But these cancer cells have a unique characteristic of relying on the PARP enzyme to restore the DNA for them to survive. This mechanism of cancer cells for their survivability can be halted by selectively inhibiting the PARP enzyme and Olaparib's significant role.

Uses:

1. Olaparib is used to treat advanced high-grade cancers of the ovary, fallopian tube, and peritoneum with an epithelial origin.

2. Olaparib is sensitive to platinum therapy and has been approved for maintenance therapy in cancers associated with BRCA mutation.

Dosage:

Olaparib has to be taken under a doctor's prescription.

The following are the prescribing instructions:

• The proposed dosage of Lynparza is 300 mg.

• These tablets are to be administered orally.

• It has to be taken twice daily.

• There is no specification regarding their intake of food. Hence, it can be taken with or without food.

• The tablet has to be swallowed as a whole without chewing, crushing, dissolving or dividing the tablet.

• Lynparza has to be administered along with gonadotropin-releasing hormone (GnRH) analog to patients under the treatment for metastatic castration-resistant prostate cancer (mCRPC). If not the patient must have undergone bilateral orchiectomy (surgical removal of both testicles).

• For patients with moderate renal impairment (creatinine clearance rate in the range of 31 to 50 mL per minute), it is advised to reduce the dosage of Lynparza to 200 mg, to be taken orally, twice daily.

Warning:

• Myelodysplastic Syndrome or Acute Myeloid Leukemia:

Myelodysplastic syndrome refers to a group of blood cancers where the blood cells remain immature in the bone marrow. These immature blood cells do not convert into healthy cells. Acute myeloid leukemia is one such cancer involving immature white blood cells.

Literature has shown that some patients taking Olaparib have got myelodysplastic syndrome (MDS) or acute myeloid Leukemia (AML) with an incidence rate of 1.5 %. Few cases had fatal outcomes. The hematological toxicity of the patient has to be assessed completely before starting the therapy with Olaparib. Monitoring complete blood count regularly is empirical to Olaparib therapy.

• Pneumonitis:

Pneumonitis refers to the inflammation of the lung tissue. The incidence of this condition in patients having Olaparib is said to be 0.8 %. This includes fatal cases. The patients will complain of new symptoms such as cough, difficulty in breathing, and fever. There will be abnormalities seen in the chest X-ray.

• Embryo-Fetal Toxicity:

Olaparib can have adverse effects on pregnant females. The drug's action affects the developing embryo. Animal studies have shown the toxicity of Olaparib during the period of organ development of the fetus. Based on the literature, females who are trying to conceive are advised to use effective contraception and postpone pregnancy at least for six months from the last dose of Olaparib.

• Venous Thromboembolic Events:

Olaparib causes blood clots, reduces or stops the supply of blood to major organs like the lungs (pulmonary embolism is common). These events occur with greater incidence in patients having metastatic castration-resistant prostate cancer receiving Olaparib and androgen deprivation therapy (ADT).

All the patients who are in therapy with Olaparib have to be continuously monitored for the above adverse events. In case of any, the medication has to be discontinued and appropriate treatment should be undergone to manage them immediately.

For Patients:

What Is BRCA and Its Mutation?

BRCA is a tumor suppressor gene that inhibits the development of cancer. BRCA is an acronym for breast cancer gene. They are of two types BRCA1 and BRCA2. Every human has two copies of these genes. Their purpose is to code proteins to repair the damaged DNA and support the normal growth of the breast, ovary, and prostate.

BRCA mutation refers to any structural changes in the sections of the BRCA1 and BRCA2 genes. These mutations possess a significantly higher risk of developing breast, ovarian, prostate, and pancreatic cancers. It is to be emphasized that not all of these mutations have a higher risk and even high-risk mutations do not always cause cancer. These mutations are genetically inherited and the chance of acquiring the mutated gene for a child would be 50 % from a single parent carrying the affected gene.

What Are PARP and PARP Inhibitors?

PARP means poly ADP-ribose polymerase. PARP is an essential enzyme involved in the DNA repair process. It is critical for cell formation and execution of cellular functions. Such activity of the PARP enzymes is used by the cancer cells for disease progression. Hence inhibiting PARP enzymes opened a way to treat certain cancers that do not respond well to usual treatments.

PARP inhibitors are used in adjunct with other cancer treatments to stop the repair of the damaged DNA in the cancer cells caused by chemotherapy and radiation therapy.

What to Know About Advanced Ovarian Cancer and Metastatic Breast Cancer?

Ovarian cancer is when the respective cells grow and divide abnormally without any control. These cancers have a higher risk of recurring even if the cancer cells are entirely removed from the body without any remnants. And the recurred cancer cells will be highly resistant to chemotherapy. Thus maintenance therapy will help prevent the recurrence of advanced ovarian cancer and preserve the treatment outcome of previously received chemotherapy.

Information About Olaparib:

What Is Olaparib?

Olaparib is commercially available as Lynparza. It is a prescription medicine treating adults suffering from the advanced stages of ovarian cancer, fallopian tube cancer, prostate cancer, and peritoneal cancer. The patient must have already received chemotherapy before or after surgery. They are used as a maintenance treatment to halt cancer metastasis (spread) while given in combination with other anticancer medications.

What Are the Precautions to Be Taken Before Taking Olaparib?

The healthcare professionals must be informed about the existing medical condition before taking Olaparib.

Some of the important mentions are

• Breathing problems and lung diseases.

• Kidney disorders.

• Women who are pregnant or trying to conceive.

• Breastfeeding ladies.

Also, inform the healthcare provider about the history of medications including health supplements like multivitamins and herbal formulations.

How to Take Olaparib?

Olaparib has to be taken daily. As the recommended dosage is 300 mg for the adult population one can have two tablets of Olaparib (Lynparza - 150 mg) in the morning and in the evening. So totally, it should be four tablets compiled into 600 mg of dosage as a daily limit.

• It is advisable to strictly follow the instructions given by the doctor.

• Do not take the tablet with an extra dosage.

• Do not change the dosage.

• Do not skip or stop the tablet until advised.

• Report immediately if there are side effects.

• Take the tablet orally with a gap of 12 hours.

The contained instruction is to avoid grapes and oranges while taking Olaparib because these are said to be factors that increase the level of Olaparib in the body.

What Are the Side Effects of Olaparib?

Some of the common side effects include

• Nausea or vomiting.

• Dizziness.

• Loose stools.

• Reduction in blood cells (especially red blood cells).

• Taste alteration.

• Cough.

• Digestion issues.

• Heartburn.

• Lethargy.

What Should Be Done When You Miss a Dose?

When you miss taking a tablet of Olaparib on time, it is suggested not to take the dose at the time you remember to compensate for the missed dosage. Extra dosage may possess serious problems. Instead, it is advisable to have the next dose at the scheduled time.

What Should Be Done to Treat Olaparib Overdose?

If you think you have taken an overdose of Olaparib tablet, immediately seek help from the healthcare professional and rush to a nearby hospital to avoid any serious outcomes. Do not take more than four Olaparib tablets in a day. If there exists any doubt regarding the dosage or intake, clarify them with the healthcare professional.

For Doctors:

Indication:

Olaparib is indicated in the maintenance treatment of BRCA-mutated advanced or recurrent ovarian cancer, high-risk or metastatic breast cancer, metastatic pancreatic adenocarcinoma, and metastatic castration-resistant prostate cancer.

Pharmacology:

Mechanism of Action:

Olaparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, which hampers the action of PARP1, PARP2, and PARP3. The normal function of PARP is to repair DNA that is utilized by cancer cells for their growth and spread. Studies have shown that Olaparib decreased the growth of certain cancer cells in vitro, both when given as monotherapy or after chemotherapy. The toxicity to the cells and their anticancer activity increased in particular to deficiency in BRCA 1 and BRCA2 gene involvement. Thus this cytotoxicity action of Olaparib happens from its inhibition of PARP enzymes causing DNA damage in the cancer cells.

Pharmacodynamics:

Studies assessed cardiac electrophysiology after the intake of Olaparib. It was concluded that there were no changes in the QT interval.

Chemical Taxonomy:

Ingredients:

Active Ingredient:

The only active ingredient present in Lynparza is Olaparib.

Inactive Ingredients:

The inactive ingredients present in the Lynparza tablet are:

• Copovidone.

• Mannitol.

• Colloidal silicon dioxide.

• Sodium stearyl fumarate.

The inactive ingredients present in the Lynparza tablet coating are

• Hypromellose.

• Polyethylene glycol.

• Titanium dioxide.

• Ferric oxide yellow and ferrosoferric oxide.

Absorption:

• After being taken orally, Olaparib is absorbed rapidly.

• The average peak concentration of Olaparib in the blood is reached typically within 1.5 hours.

• The concentration of Olaparib increases steadily at the dosage of 25 mg to 450 mg.

• High-fat meals decrease the absorption rate of Olaparib and the time for maximum concentration is delayed by 2.5 hours, but the extent of absorption is not altered.

Distribution:

• The average distribution volume for Olaparib is around 158 L plus or minus 136 L after a single dose of 300 mg.

• The protein binding efficiency of Olaparib is approximately 82 %.

Metabolism:

• Olapairb undergoes oxidation reaction.

• The resultant components will undergo subsequent conjugation with glucuronide or sulfate.

• Olaparib is primarily metabolized by cytochrome P450 (CYP3A4 or 5) enzymes.

• The majority of circulatory Olaparib was metabolized and the unchanged drug accounted for around 15 % in urine and 6 % in feces.

Elimination:

• The average half-life period of Olaparib in plasma is 14.9 plus or minus 8.2 hours.

• A single 300 mg dose of Olaparib had a plasma clearance of 7.4 plus or minus 3.9 L per hour.

• Most of the ingested olaparib was eliminated as metabolites.

• The recovered radioactivity at the end of a week was 44 % through the urine and 42 % through the feces.

Toxicity:

There is no relevant information or evidence regarding the overdose or toxicity of Olaparib. The lethal dose (LD50 - the amount required to cause 50 % death in a given population) of Olaparib found in rats was 240-300 mg/kg.

Warning and Precaution:

• Few patients under Olaparib (Lynparza) monotherapy developed myelodysplastic syndrome or acute myeloid leukemia with an incidence of less than 1.5 %. The duration of the drug therapy was between six months to two years. However, most of the patients have already received chemotherapy or radiotherapy. Hence there is a higher chance of toxicity to hematological cells. Before therapy with Olaparib, it is necessary to check the complete blood count for cytopenia, which must be monitored every month throughout the therapy. If leukemia is confirmed on further investigations, it is empirical to discontinue the treatment with Olaparib.

• Some fatal cases (less than 1%) of pneumonitis have occurred with Olaparib therapy. During therapy, discontinue Olaparib therapy immediately if the patients confer any respiratory ailments like dyspnea, cough, fever, or radiological abnormalities. The condition has been assessed, and the patients are treated accordingly for pneumonitis.

• Animal studies have shown Olaparib is lethal to fetuses when taken by pregnant women. The drug interferes with the organ development of the embryo. Hence patients are advised to use effective contraception during the treatment of Olaparib which has to be continued for six months with females and three months with males (with a female partner of reproductive potential) from the last dose of Olaparib.

Dosage and Forms:

Lynparza comes in tablet form and is a prescription medicine that is administered orally.

They are available in two dosage forms:

• 150 mg - green or greenish-gray in color with biconvex shape, film-coated with debossed letters of ‘OP150’ on one side, and the other side is left plain.

• 100 mg - yellow to dark yellow with biconvex shape, film-coated with debossed letters of ‘OP100’ on one side, and the other side is left plain.

Administration of the Drug:

• Lynparza should be taken twice daily.

• The suggested dosage of the drug is 300 mg (two tablets of 150 mg) for a spell and a total of 600 mg per day.

• The tablet has to be swallowed as a whole without chewing, crushing, dissolving, or dividing the tablet.

• The tablet can be taken before or after food.

Dose Adjustment During Administration:

• If patients present with adverse reactions, consider reducing the dosage of Olaparib to 250 mg, compiling the total dose to 500 mg daily.

• For patients taking strong cytochrome P450 (CYP3A) inhibitors, consider reducing the dosage to 100 mg for the concomitant usage of Olaparib to an equivalent dosage of 200 mg daily.

• For patients taking moderate cytochrome P450 (CYP3A) inhibitors, consider reducing the dosage to 150 mg for the concomitant usage of Olaparib to an equivalent dosage of 300 mg per day.

• For patients having moderate renal impairment, with a creatinine clearance value of 31 to 50 ml per minute, consider reducing the dosage to 100 mg of Olaparib to an equivalent dosage of 200 mg per day.

• Patients having severe renal impairment have not been evaluated for Olaparib therapy.

Contraindications:

There is no relevant documentation reporting absolute or relative contraindication to Olaparib.

Clinical Studies for Olaparib:

1. For Maintenance Treatment of Recurrent Ovarian Cancer:

• A double-blinded, placebo-controlled trial was undertaken in patients having gBRCAm ovarian, fallopian tube, or primary peritoneal cancer.

• The patients randomly received 300 mg of Lynparza twice daily or a placebo.

• All the patients were treated earlier with platinum-based regimens.

Results - The study concluded with a significant reduction in the disease progression and improvement in the survival rate of the patients.

2. For Advanced gBRCA - Mutated Ovarian Cancer Treated With Prior Chemotherapy:

• One hundred thirty-seven patients with advanced gBRCAm ovarian cancer were selected.

• All the patients had three or more prior lines of chemotherapy drugs.

• Later the patients were given 400 mg of Lynparza twice daily as a monotherapy.

• The overall response and efficacy improved significantly.

3. For Treatment of gBRCAm HER2-Negative Metastatic Breast Cancer:

• This study selected patients with gBRCAm HER2- negative metastatic breast cancer.

• All patients randomly received 300 mg of Lynparza or chemotherapy.

• Results - There was a significant improvement in the disease halt and survival rate in the Lynparza arm compared to the chemotherapy arm.

Drug Interactions:

• Olaparib, when combined with other myelosuppressive drugs, can enhance myelosuppressive toxicity.

• CYP3A majorly metabolizes Olaparib in the body. Avoid using them with CYP3A inhibitors since they increase the overall concentration of Olaparib in the body. Grapefruit, grapefruit juice, and Seville orange are considerably CYP3A inhibitors.

• CYP3A inducer drugs are avoided since they diminish the overall Olaparib drug concentration in the plasma.

Other Specifications:

Olaparib in Pregnant and Lactating Women:

Olaparib poses a significant risk to the fetus when given to pregnant women. The potential hazard includes birth defects (interfere with organogenesis) and miscarriage. Patients who are about to receive Olaparib are advised to use contraception for at least six months from the last dose of Olaparib. Women are advised not to breastfeed during the treatment of Olaparib and at least a month from the last dose of the drug, owing to the adverse effects on the infants.

Olaparib in Pediatric Patients:

There is no clinical evidence to demonstrate the safety and efficacy of Olaparib in pediatric patients.

Olaparib in Geriatric Patients:

Literature shows no overall difference in the safety and effectiveness of Olaparib between younger and older patients.

Olaparib in Renal Impairment Patients:

Patients with mild renal impairment need no adjustment in the initial dosage of Olaparib. Dose reduction of 200 mg of Olaparib is advised in patients with moderate renal impairment. There is no relevant data on patients with severe renal impairment.

Olaparib in Hepatic Impairment Patients:

Patients with mild hepatic impairment need no adjustment in the initial dosage of Olaparib. There is no relevant data on patients with moderate or severe renal impairment.