Talazoparib

380.3508664

380.35

9QHX048FRV

C95733

L01XX|L - Antineoplastic and immunomodulating agents

84.2

1.4

1.63

1.775

P201, P202, P260, P264, P270, P281, P308+P313, P314, P405, P501

H341

|Danger|H341 (100%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]|P201, P202, P260, P264, P270, P281, P308+P313, P314, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P260, P264, P270, P301+P310, P314, P321, P330, P405, and P501

Talazoparib is clastogenic due to its pharmacological mechanism. Talazoparib does not appear to be mutagenic and no data is available on carcinogenicity. In repeat-dose toxicity studies up to 3-months duration at doses ≥0.04 mg/kg/day in rats and ≥0.01 mg/kg/day in dogs resulted in decreased organ weights, luminal cellular debris, reduced sperm, and degeneration/atrophy in the testis and epididymis. These doses were equivalent to approximately 1.0 times and 0.2 times normal human exposure. Follicular atresia of the ovary was observed in rats at doses ≥1 mg/kg/day, equivalent to 9.5 times normal human exposure. While no fertility data exists these results suggest a potential for reduced fertility due to talazoparib exposure.

Elevations in serum aminotransferase levels are common during talazoparib therapy occurring in 33% of patients, but rising above 5 times the upper limit of the normal range in only 1%. The elevations are generally transient and not associated with symptoms or jaundice. Furthermore, similar rates of aminotransferase elevations were reported in control, comparator arms. Talazoparib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with using talazoparib and other PARP inhibitors, their potential for causing liver injury is not well defined.

Talazoparib is 74% bound to plasma proteins and independent of drug concentration.

Talazoparib is indicated for the treatment of deleterious or suspected deleterious germline BRCA mutated, HER2 negative locally advanced or metastatic breast cancer in adults.|FDA Label|Talzenna is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2 mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy.

Talazoparib is an orally available small molecule inhibitor of the DNA repair enzyme poly ADP-ribose polymerase (PARP) which is used as an antineoplastic agent in the treatment of selected cases of breast cancer. Talazoparib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.

Antineoplastic Agents

Talazoparib prevents PARP-mediated repair of DNA damage in cancer cells, allowing accumulation of damage and PARP-DNA complexes. Repair related errors by error prone secondary repair pathways may also contribute to the cytotoxicity of talazoparib.

Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES. (See all compounds classified as Poly(ADP-ribose) Polymerase Inhibitors.)

Talzenna capsules have a reach peak plasma concentration in 1-2 h. If taken with a high fat meal, Cmax decreases by 43%, Tmax increases by 1-4 h, and no change occurs in AUC.|64.7% of talazoparib is excreted in the urine with 54.6% as unchanged drug. 19.7% is eliminated in the feces with 13.6% as unchanged drug.|Talazoparib has a mean apparent volume of distribution of 420 L.|The mean apparent oral clearance of talazoparib is 6.45 L/h with an inter-individual variability of 31.1%. Apparent oral clearance is reduced by 14.4% in patients with mild renal impairment while mild hepatic impairment has no effect. No data is available in patients with moderate to severe renal or hepatic impairment.

Talazoparib is metabolized via mono-oxidation, dehydrogenation, cysteine conjugation of a mono-desfluoro metabolite, and glucuronide conjugation. The overall contribution of metabolism to talazoparib elimination is minimal.

The mean terminal plasma half life of Talzenna capsules is 90 h with a standard deviation of 58 h.

Talazoparib binds to and inhibits PARP1 and PARP2 at the NAD+ binding site with a Ki of 1.2 and 0.87 nM, respectively. The inhibitory effect on PAR synthesis has an EC50 of 2.51 nM.

BMN 673

Human drugs -> Talzenna -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients