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

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...

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Autores principales: Durairaj, Chandrasekar, Chakrabarti, Jayeta, Ferrario, Cristiano, Hirte, Holger W., Babu, Sunil, Piha-Paul, Sarina A., Plotka, Anna, Hoffman, Justin, Shi, Haihong, Wang, Diane D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249284/
https://www.ncbi.nlm.nih.gov/pubmed/33686631
http://dx.doi.org/10.1007/s40262-020-00983-y
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author Durairaj, Chandrasekar
Chakrabarti, Jayeta
Ferrario, Cristiano
Hirte, Holger W.
Babu, Sunil
Piha-Paul, Sarina A.
Plotka, Anna
Hoffman, Justin
Shi, Haihong
Wang, Diane D.
author_facet Durairaj, Chandrasekar
Chakrabarti, Jayeta
Ferrario, Cristiano
Hirte, Holger W.
Babu, Sunil
Piha-Paul, Sarina A.
Plotka, Anna
Hoffman, Justin
Shi, Haihong
Wang, Diane D.
author_sort Durairaj, Chandrasekar
collection PubMed
description 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 m(2)) 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 (AUC(0–24)) and maximum observed plasma concentration (C(max)) 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 AUC(0–24), and a 11.1%, 31.6%, and 89.3% increase in talazoparib C(max), 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-020-00983-y.
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spelling pubmed-82492842021-07-20 The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors Durairaj, Chandrasekar Chakrabarti, Jayeta Ferrario, Cristiano Hirte, Holger W. Babu, Sunil Piha-Paul, Sarina A. Plotka, Anna Hoffman, Justin Shi, Haihong Wang, Diane D. Clin Pharmacokinet Original Research Article 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 m(2)) 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 (AUC(0–24)) and maximum observed plasma concentration (C(max)) 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 AUC(0–24), and a 11.1%, 31.6%, and 89.3% increase in talazoparib C(max), 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-020-00983-y. Springer International Publishing 2021-03-09 2021 /pmc/articles/PMC8249284/ /pubmed/33686631 http://dx.doi.org/10.1007/s40262-020-00983-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Durairaj, Chandrasekar
Chakrabarti, Jayeta
Ferrario, Cristiano
Hirte, Holger W.
Babu, Sunil
Piha-Paul, Sarina A.
Plotka, Anna
Hoffman, Justin
Shi, Haihong
Wang, Diane D.
The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title_full The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title_fullStr The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title_full_unstemmed The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title_short The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors
title_sort effect of renal impairment on the pharmacokinetics and safety of talazoparib in patients with advanced solid tumors
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249284/
https://www.ncbi.nlm.nih.gov/pubmed/33686631
http://dx.doi.org/10.1007/s40262-020-00983-y
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