DESCRIPTION
MECHANISM OF ACTION
• Small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3.
• Inhibition of PARP enzymatic activity, with increased formation of PARP-DNA complexes, results in cell death.
• Enhanced antitumor activity in tumors that are BRCA-deficient.
ABSORPTION
Oral absorption is rapid, with peak plasma concentrations achieved between 1 and 3 hours after administration. Food with high fat content can slow the rate of absorption but does not alter systemic drug exposure.
DISTRIBUTION
Fairly extensive binding of olaparib to plasma proteins (82%). With daily dosing, steady-state blood levels are achieved in about 3–4 days.
INDICATIONS
1. FDA-approved for the treatment of deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer following treatment with three or more lines of chemotherapy.
2. FDA-approved for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy.
3. FDA-approved for the treatment of deleterious or suspected deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer that has been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor–positive breast cancer should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy.
4. FDA-approved for the maintenance treatment of deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to first-line platinum-based chemotherapy.
DOSAGE RANGE
1. Advanced ovarian cancer: 300 mg PO bid. The previous recommended capsule dose was 400 mg PO bid.
2. Ovarian cancer maintenance therapy: 300 mg PO bid.
3. Metastatic breast cancer: 300 mg PO bid.
DRUG INTERACTION 1
Drugs that stimulate liver microsomal CYP3A4 enzymes, including phenytoin, carbamazepine, rifampin, phenobarbital, and St. John’s Wort—These drugs may increase the metabolism of olaparib, resulting in lower drug levels and potentially reduced clinically activity.
DRUG INTERACTION 2
Drugs that inhibit liver microsomal CYP3A4 enzymes, including ketoconazole, itraconazole, erythromycin, and clarithromycin—These drugs may reduce the metabolism of olaparib, resulting in increased drug levels and potentially increased toxicity.
SPECIAL CONSIDERATIONS
1. Olaparib has not been studied in patients with liver impairment, and there are no formal recommendations for dosing in this setting.
2. No dose modification is needed in patients with mild renal impairment (CrCl 50–80 mL/min). Olaparib has not been studied in patients
with moderate or severe renal impairment, and there are no formal recommendations for dosing in this setting.
3. Olaparib capsules should be swallowed whole and should not be chewed, dissolved, or crushed.
4. Olaparib capsules are in the process of being phased out, and only olaparib tablets will be available. Patients need to be educated that olaparib tablets and capsules are NOT interchangeable.
5. Closely monitor for new onset of pulmonary symptoms, and if pneumonitis is confirmed, olaparib therapy should be stopped.
6. Closely monitor blood counts at monthly intervals. For prolonged hematologic toxicities, interrupt therapy, and monitor CBCs on a weekly basis until recovery. If blood counts have not recovered within 4 weeks, bone marrow analysis and peripheral blood for cytogenetics should be performed to rule out the possibility of MDS/AML.
7. Pregnancy category D.
TOXICITY 1
Fatigue, anorexia, and asthenia.
TOXICITY 2
Increased risk of infections, with nasopharyngitis, pharyngitis, and URI.
TOXICITY 3
Pneumonitis with dyspnea, fever, cough, and wheezing.
TOXICITY 4
GI side effects in the form of nausea/vomiting, abdominal pain, diarrhea, and constipation.
TOXICITY 5
Arthralgias and myalgias.
TOXICITY 6
Myelosuppression with anemia, thrombocytopenia, and neutropenia.
TOXICITY 7
MDS and AML.
SPECIFICATION
Login To Comment