A validated LC-MS/MS method for determination of neuro-pharmacokinetic behavior of niraparib in brain tumor patients.
J Pharm Biomed Anal
; 245: 116150, 2024 Aug 01.
Article
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| MEDLINE
| ID: mdl-38657366
ABSTRACT
Niraparib is a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) with high specificity for isoforms 1 and 2. It has been approved by the U.S. Food and Drug Administration for ovarian cancer maintenance therapy and is currently under development for various cancers, including glioblastoma. To assess central nervous system (CNS) penetration of niraparib in glioblastoma patients, a novel bioanalytical method was developed to measure total and unbound niraparib levels in human brain tumor tissue and cerebrospinal fluid (CSF). The method was validated using plasma as a surrogate matrix over the concentration range of 1-10,000â¯nM on an LC-MS/MS system. The MS/MS detection was conducted in positive electrospray ionization mode, while chromatography was performed using a Kinetex™ PS C18 column with a total 3.5-minute gradient elution run time. The maximum coefficient of variation for both intra- and inter-day precision was 10.6%, with accuracy ranging from 92.8% - 118.5% across all matrices. Niraparib was stable in human brain homogenate for at least 6â¯hours at room temperature (RT) and 32 days at -20°C, as well as in stock and working solutions for at least 21â¯hours (RT) and 278 days (4°C). Equilibrium dialysis experiments revealed the fractions unbound of 0.05 and 0.16 for niraparib in human brain and plasma, respectively. The validated method is currently employed to assess niraparib levels in human glioblastoma tissue, CSF, and plasma in an ongoing trial on newly diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513). Initial results of calculated total (Kp) and unbound (Kp,uu) tumor-to-plasma partition coefficients indicate significant brain penetration ability of niraparib in glioblastoma patients.
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MEDLINE
Asunto principal:
Piperidinas
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Neoplasias Encefálicas
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Espectrometría de Masas en Tándem
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Inhibidores de Poli(ADP-Ribosa) Polimerasas
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Indazoles
Idioma:
En
Revista:
J Pharm Biomed Anal
Año:
2024
Tipo del documento:
Article