Chemical formula: C₁₉H₁₄F₂N₆O Molecular mass: 380.359 g/mol PubChem compound: 44819241
Talazoparib is an inhibitor of PARP enzymes, PARP1, and PARP2. PARP enzymes are involved in cellular DNA damage response signalling pathways such as DNA repair, gene transcription, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription, thereby resulting in apoptosis and/or cell death.
Treatment of cancer cell lines that are harbouring defects in DNA repair genes with talazoparib single agent leads to increased levels of γH2AX, a marker of double stranded DNA breaks, and results in decreased cell proliferation and increased apoptosis. Talazoparib anti-tumour activity was also observed in a patient-derived xenograft (PDX) BRCA mutant breast cancer model where the patient was previously treated with a platinum-based regimen. In this PDX model talazoparib decreased tumour growth and increased γH2AX level and apoptosis in the tumours.
The effect of talazoparib on cardiac repolarisation was evaluated using time-matched electrocardiograms (ECGs) in assessing the relationship between the change of the QT interval corrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrations in 37 patients with advanced solid tumours. Talazoparib did not have a clinically relevant effect on QTc prolongation at the maximum clinically recommended dose of 1 mg once daily.
Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to 2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparib to patients, the geometric mean (% coefficient of variation [CV%]) area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was in the range of 126 (107) ng•hr/mL to 208 (37) ng•hr/mL and 11 (90) ng/mL to 19 (27) ng/mL, respectively. Following repeated daily dosing, plasma talazoparib concentrations reached steady-state within 2 to 3 weeks. The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.3 to 5.2. Talazoparib is a substrate of P-gp and BCRP transporters.
Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing. The absolute bioavailability study has not been conducted in humans. However, based on urinary excretion data the absolute bioavailability is at least 41% with fraction absorbed of at least 69% (see Elimination). No significant effect of acid-reducing agents on talazoparib exposure is expected, given sufficient solubility of talazoparib at all pHs between 1 and 6.8. Twenty-eight percent (28%) of the patients in the pivotal study were taking acid-reducing agents, mainly proton pump inhibitors.
Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oral dose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean Cmax of talazoparib was decreased by approximately 46%, the median Tmax was delayed from 1 to 4 hours, while the AUC inf was not affected. Based on these results, talazoparib can be administered with or without food.
The population mean apparent volume of distribution (Vss/F) of talazoparib was 420 L. In vitro, talazoparib is approximately 74% bound to plasma proteins with no concentration dependence over the concentration range of 0.01 μM to 1 μM.
Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of a single 1 mg dose of [14C]talazoparib to humans, no major circulating metabolites were identified in plasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites that individually represented more than 10% of the administered dose were recovered in the urine or faeces.
In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters (P-gp, BCRP, organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationic transporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP], multidrug and toxin extrusion [MATE]1 and MATE2-K) at clinically relevant concentrations.
In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.
Renal elimination of unchanged drug (passive filtration and active secretion) is the major route of talazoparib elimination. P-gp is likely involved in talazoparib active renal secretion. The mean (±standard deviation) terminal plasma half-life of talazoparib was 90 (±58) hours and the population mean (inter-subject variability) apparent oral clearance (CL/F) was 6.5 (31%) L/h in cancer patients. In 6 female patients given a single oral dose of [14C]talazoparib, a mean of 69% (±8.6%) and 20% (±5.5%) of the total administered radioactive dose was recovered in urine and faeces, respectively. Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 55% of the administered dose, while unchanged talazoparib recovered in the faeces accounted for 14%.
A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of age (ranging from 18 to 88 years), sex (53 males and 437 females), and body weight (ranging from 35.7 kg to 162 kg) on the PK of talazoparib. The results have shown that age, sex, and body weight had no clinically relevant effect on the PK of talazoparib.
Based on a population PK analysis that included 490 patients, where 41 patients were Asian and 449 patients were Non-Asian (361 White, 16 Black, 9 Others, and 63 Not reported), talazoparib CL/F was higher in Asian patients compared to Non-Asian patients, leading to 19% lower exposure (AUC) in Asian patients.
Pharmacokinetics of talazoparib have not been evaluated in patients <18 years of age.
Based on a population PK analysis that included 490 patients, where 132 patients had mild renal impairment (60 mL/min≤ CrCL <90 mL/min), 33 patients had moderate renal impairment (30 mL/min≤ CrCL <60 mL/min), and 1 patient had severe renal impairment (CrCL <30 mL/min), talazoparib CL/F was decreased by 14% and 37% in patients with mild and moderate renal impairment, respectively, when compared to patients with normal renal function (CrCL ≥90 mL/min). Insufficient data are available to estimate the impact of severe renal impairment on talazoparib CL/F in this patient population. The PK of talazoparib have not been studied in patients requiring haemodialysis.
Based on a population PK analysis that included 490 patients, where 118 patients had mild hepatic impairment (total bilirubin ≤1.0 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib have not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).
Carcinogenicity studies have not been conducted with talazoparib.
Talazoparib was not mutagenic in a bacterial reverse mutation (Ames) test. Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo micronucleus assay in rats at exposures similar to clinically relevant doses. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of talazoparib, indicating the potential for genotoxicity in humans.
In repeat-dose toxicity studies in rats and in dogs, the main findings at subtherapeutic exposures included bone marrow hypocellularity with dose-dependent decrease in haematopoietic cells, depletion of lymphoid tissue in multiple organs and atrophy and/or degenerative changes in testes, epididymis and seminiferous tubules. Additional findings at higher exposures included dose-dependent increase in apoptosis/necrosis in the gastrointestinal (GI) tract, liver and ovary. Most of the histopathologic findings were generally reversible while the testes findings were partially reversible after 4 weeks of dosing cessation. These toxicity findings are consistent with the pharmacology of talazoparib and its tissue distribution pattern.
In an embryo-foetal development study in rats, talazoparib resulted in embryo-foetal death, foetal malformation (depressed eye bulge, small eye, split sternebrae, fused cervical vertebral arch) and structural variations in bones at a maternal systemic AUC24 exposure approximately 0.09-fold the relevant human exposure at the recommended dose.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
