The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors

Abstract

Background: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment.

Methods: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m2) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) and maximum observed plasma concentration (Cmax) at steady state (Day 22). Safety and tolerability were also investigated.

Results: Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC0-24, and a 11.1%, 31.6%, and 89.3% increase in talazoparib Cmax, respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups.

Conclusions: Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment.

Clinical trials registration: NCT02997163.

Conflict of interest statement

Chandrasekar Durairaj, Jayeta Chakrabarti, Anna Plotka, Justin Hoffman, Haihong Shi, and Diane D. Wang are employees of Pfizer and receive stock and stock options as part of their employment. Cristiano Ferrario has received consulting fees from Astellas, Bayer, Eli Lilly, Novartis, Pfizer, and Roche, and research funding from Astellas, AstraZeneca, Merck, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Zymeworks. Holger W. Hirte has no disclosures to declare. Sunil Babu has received honoraria from Alexion Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, and Lilly; consulting fees from Alexion Pharmaceuticals, Argenx, AstraZeneca, Boehringer Ingelheim, and Bristol-Myers Squibb; speaker fees from Alexion Pharmaceuticals; research/grant funding (through his institution) from Abbvie, Alexion Pharmaceuticals, Amgen, Argenx, AstraZeneca/Medimmune, Bristol-Myers Squibb, Genentech/Roche, Janssen Oncology, Lilly, Merck, Nektar, Novartis, Sanofi, Syndax, and TG Therapeutics; and travel/accommodation expenses from Alexion Pharmaceuticals, Bristol-Myers Squibb, and Lilly. Sarina A. Piha-Paul has received research/grant funding (through her institution) from AbbVie, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Daichi Sanko, Eli Lilly, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., TransThera Bio, and XuanZhu Biopharma. NCI/NIH Core Grant, P30CA016672 (CCSG Shared Resources).

Figures

Fig. 1

Median talazoparib plasma concentration following multiple oral doses of talazoparib in patients with varying degrees of renal function (Day 22, PK population). PK pharmacokinetics

Fig. 2

Regression and 90% CI of natural log-transformed plasma talazoparib a AUC0–24 and b CL/F versus CLcr (mL/min) following administration of multiple oral doses of talazoparib in patients with varying degrees of renal impairment (Day 22, PK analysis population). AUC0–24 area under the concentration-time curve from 0 to 24 h, CI confidence interval, CL/F apparent oral clearance, CLcr creatinine clearance, PK pharmacokinetics