Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment

Abstract

This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function.Methods: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients.Results: Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug.Conclusions: Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.The authors confirm that the PI for this study is Dr Wainberg and that he had direct clinical responsibility for patients.Clinical trials registration: NCT02997176.

Dose Adjustment of Poly (ADP‑Ribose) Polymerase Inhibitors in Patients with Hepatic or Renal Impairment

“…39 Based on the PK data, dose adjustment is not required for talazoparib and veliparib in patients with varying degrees of hepatic impairment, but the dose should be modified in patients with moderate or severe renal impairment. [42][43][44] These results are consistent with the major role of renal excretion in the clearance of talazoparib and veliparib. 23,30 In practice, it is difficult to conduct a clinical study to evaluate the drug efficacy and safety in patients with severe hepatic or renal impairment.…”

“…Based on the results of the population PK analysis and clinical studies, mild, moderate and severe hepatic impairment had no significant impact on the clearance of talazoparib. 42 Therefore, no dose adjustment is recommended for patients with various degrees of hepatic impairment. 30,31,42 Based on the PK study, patients with mild, moderate, and severe renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC, and an 11.1%, 31.6%, and 89.3% increase in talazoparib C max , respectively.…”

“…42 Therefore, no dose adjustment is recommended for patients with various degrees of hepatic impairment. 30,31,42 Based on the PK study, patients with mild, moderate, and severe renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC, and an 11.1%, 31.6%, and 89.3% increase in talazoparib C max , respectively. 43 Therefore, no dose adjustment is required for patients with mild renal impairment, but the recommended dose of talazoparib is 0.75 mg once daily for patients with moderate renal impairment, and 0.5 mg once daily for patients with severe renal impairment.…”

Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology

“…No effect of mild, moderate, or severe hepatic impairment was observed on talazoparib pharmacokinetics. Therefore, no dose adjustments are required [ 106 , 108 ].…”

In Silico Investigation of the Molecular Mechanism of PARP1 Inhibition for the Treatment of BRCA-Deficient Cancers

“…Interestingly, admetSAR2 predicated a better oral bioavailability of MTR-106 (0.5857) relative to talazoparib (0.5429), in line with the bioavailability radar of MTR-106, which showed that all the bioavailability features of the MTR-106 were within the optimum ranges, except for the size (molecular weight of 525.62 g/mol; Figure S8 ). The predicted ADMET profiles of both compounds agree with their in vivo bioactivities and pharmacokinetic properties [ 15 , 27 , 62 ].…”