Lynparza

Uses

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor used as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Lynparza is also used to associated treatment for these conditions: Fallopian Tube Cancer, Malignant Peritoneal Neoplasm, Metastatic Breast Cancer, Ovarian Epithelial Cancer, Primary Peritoneal Cancer, Advanced deleterious germline or somatic BRCA-mutated advanced epithelial ovarian cancer, Advanced deleterious germline or somatic BRCA-mutated fallopian tube cancer, Advanced deleterious germline or somatic BRCA-mutated peritoneal cancer, Refractory Advanced Ovarian Cancer

How Lynparza works

Lynparza 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 . Lynparza 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 .

Dosage

Lynparza dosage

Recommended dose is 400 mg taken orally twice daily with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption of treatment or dose reduction.

For moderate renal impairment (CrCl 31-50 mL/min), reduce dose to 300 mg twice daily

Side Effects

Most common adverse reactions (≥20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort.

Most common laboratory abnormalities (≥25%) were increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in absolute neutrophil count, and decrease in platelets

Toxicity

The most commonly reported side effects reported during clinical trials included cough, constipation, dysgeusia, 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 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 Label . Patients should be monitored for new or worsening respiratory symptoms such as dyspnea, fever, cough, or wheezing . Lynparza was found to be teratogenic and causes embryo-fetal toxicity in rats . It should, therefore, be avoided during pregnancy and its use should be combined with effective contraception during treatment .

Precaution

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): occurred in patients exposed to Lynparza, and the majority of reports were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed.

Pneumonitis: occurred in patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed.

Embryo-Fetal Toxicity: Lynparza can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception

Interaction

CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the dose.

CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of olaparib, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of olaparib and may reduce its serum concentration.
• Take with or without food.

[Major] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of olaparib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In a drug interaction study with 57 patients, olaparib systemic exposure (AUC) was increased approximately 2.7-fold by the potent CYP450 3A4 inhibitor itraconazole.

Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that a moderate inhibitor (fluconazole) may increase the AUC of olaparib by 2-fold.

The interaction has not been studied with grapefruit juice.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to olaparib may increase the risk of adverse effects such as hematologic toxicity, nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain or discomfort.

MANAGEMENT: Patients treated with olaparib should avoid consumption of grapefruit, grapefruit juice, starfruit (carambola), and Seville oranges.

Lynparza Drug Interaction

Moderate: naproxen, duloxetine, doxorubicin liposomal, gemcitabineUnknown: amphetamine / dextroamphetamine, ibuprofen, apixaban, levothyroxine, loperamide, levothyroxine, dronabinol, magnesium hydroxide, oxycodone, acetaminophen, bioflavonoids, vitamin a topical, montelukast, cholecalciferol, alprazolam, rivaroxaban

Lynparza Disease Interaction

Moderate: hematologic toxicities, hepatic impairment, pulmonary abnormality, renal impairment

Volume of Distribution

After administration of a dose of 100 mg/kg, the reported volume of distribution was of 40.3 L.

Elimination Route

Following oral administration, the absorption of olaparib is very rapid and can reach a peak concentration ranging between 4.7 and 9.1 mcg/ml after 1-3 hours. The reported AUC of olaparib after a dose of 200 mg is of 25.8 mcg.h/L and this AUC can be increased by 26% with constant administration. The consumption of a high-fat diet with olaparib can only decrease the tmax but do not have an effect in the peak concentration.

Half Life

The reported elimination half-life ranges between 5 to 11 hours.

Clearance

The total clearance of olaparib was reported to be 4.6 L/h.

Elimination Route

From the administered dose, approximately 86% of the administered dose is recovered after 7 days from which 44% is found in the urine and 42% is obtained in feces.

Pregnancy & Breastfeeding use

Lactation: No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.

Pregnancy: Based on findings in animals and its mechanism of action, Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug associated risk.

Contraindication

None

Storage Condition

Store at 25ºC

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