TY - JOUR
T1 - The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
AU - Durairaj, Chandrasekar
AU - Chakrabarti, Jayeta
AU - Ferrario, Cristiano
AU - Hirte, Holger W.
AU - Babu, Sunil
AU - Piha-Paul, Sarina A.
AU - Plotka, Anna
AU - Hoffman, Justin
AU - Shi, Haihong
AU - Wang, Diane D.
N1 - Funding Information:
Medical writing support was provided by Katharine Howe, PhD, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
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U2 - 10.1007/s40262-020-00983-y
DO - 10.1007/s40262-020-00983-y
M3 - Article
C2 - 33686631
AN - SCOPUS:85102256582
SN - 0312-5963
VL - 60
SP - 921
EP - 930
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 7
ER -