In Preclinical Studies, ZEJULA-Induced Cytotoxicity Was Observed in Tumor Cell Lines With or Without Deficiencies in BRCA1/21
ZEJULA is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, which play a role in DNA repair.1 In vitro studies suggest that ZEJULA's cytotoxic effects may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death.1
BRCA1/2, breast cancer susceptibility genes 1 and 2.
ZEJULA Inhibits PARP1 and PARP2, Leading to Cancer Cell Death in Pre-Clinical Studies1
PARP inhibition interferes with DNA repair, leading to accumulation of single-strand breaks (SSBs).1,2
SSBs become double-strand breaks (DSBs), which are not repaired due to deficient DNA repair pathways present in many ovarian tumors.3
Persistent DSBs that cannot be repaired lead to programmed cell death.3
ZEJULA is selective for PARP1 and PARP2 compared to other PARP isoforms and other non-PARP targets.4
The clinical significance of in vitro studies is unknown. Mechanism of action statements are not meant to imply clinical efficacy.
DSB, double-strand break; PARP, poly(ADP-ribose) polymerase; SSB, single-strand break.
Preclinical studies suggest the activity of PARP inhibitors depends on tumor exposure and subsequent PARP1/2 inhibition.5
- Tumor cells carrying a BRCA mutation have been shown to be significantly more sensitive to PARP inhibition than tumors that do not carry a BRCA mutation6
- It is hypothesized that in tumors without a BRCA mutation, PARP inhibitors may need to achieve higher tumor concentrations for effect6
Pharmacologic Properties of ZEJULA
ZEJULA has high bioavailability and extensive tissue distribution, as well as a long half-life1
Absolute bioavailability of ≈73%, indicating minimal first-pass effect
Concentrates in Tissue1
Extensive tissue distribution, with a Vd/F of 1,220 L
Mean half-life of 36 hours, allowing for once-daily dosing
BRCA, breast cancer susceptibility gene; PARP, poly(ADP-ribose) polymerase; Vd/F, apparent volume of distribution.
The Distinct Pharmacology of ZEJULA
Watch the following videos to learn more about the therapeutic rationale behind PARP inhibition and aspects of how ZEJULA behaves in the body.
References: 1. ZEJULA [package insert]. Waltham, MA: Tesaro, Inc; 2017. 2. Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992;356:356-358. 3. Dale Rein I, Solberg Landsverk K, Micci F, Patzke S, Stokke T. Replication-induced DNA damage after PARP inhibition causes G2 delay, and cell line-dependent apoptosis, necrosis and multinucleation. Cell Cycle. 2015;14(20):3248-3260. 4. Data on file. TESARO, Inc. 5. Ricks TK, Chiu HJ, Ison G, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol. 2015;5:222. 6. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.