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1.
J Pharm Biomed Anal ; 245: 116140, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38701533

RESUMO

Ipilimumab is an immune checkpoint inhibitor of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Ipilimumab has become part of the standard of care for different types of cancer. The efficacy of these treatments is limited due to immune-related toxicity and high economic costs. Dose rationalization studies based on pharmacokinetic data may help to address these limitations. For this purpose, more sensitive analytical methods are needed. We report the development and validation of the first enzyme-linked immunosorbent assay (ELISA) for sensitive determination of ipilimumab concentrations in human serum, plasma, cerebrospinal fluid (CSF), and milk. Our assay is based on the specific capture of ipilimumab by immobilized CTLA-4. The lower limit of quantifications of ipilimumab in serum, plasma, and milk are 50 ng/mL and 10 ng/mL in CSF. The ELISA method showed long-term storage stability for at least one year at -80°C and was successfully cross-validated with ultraperformance liquid chromatography coupled with tandem mass spectrometry. The ELISA method is reliable, relatively inexpensive, and can be used in serum, plasma, CSF, and milk from patients treated with ipilimumab, as evidenced by the analysis of real clinical samples.


Assuntos
Ensaio de Imunoadsorção Enzimática , Ipilimumab , Humanos , Ipilimumab/líquido cefalorraquidiano , Ipilimumab/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Animais , Leite/química , Espectrometria de Massas em Tandem/métodos , Antígeno CTLA-4/antagonistas & inibidores , Reprodutibilidade dos Testes , Limite de Detecção
2.
BMC Cancer ; 19(1): 519, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146733

RESUMO

BACKGROUND: Recently, two phase II trials showed intracranial activity of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with melanoma brain metastases. However, it is generally assumed that large molecules like monoclonal antibodies nivolumab and ipilimumab cannot penetrate and pass an intact blood brain barrier (BBB). In this systematic review we provide a pharmacodynamic and pharmacokinetic consideration of the clinical activity of the immune checkpoint inhibitors nivolumab and ipilimumab in melanoma brain metastases. METHODS: Pubmed was systematically searched for prospective phase II and III studies on nivolumab and ipilimumab in melanoma brain metastases and cerebrospinal fluid (CSF) levels of nivolumab and ipilimumab. Results were discussed and a perspective on the pharmacodynamics and pharmacokinetics for the intracranial activity of these agents was given. RESULTS: Two phase II studies with the combination nivolumab and ipilimumab and one phase II study with ipilimumab monotherapy in melanoma brain metastases were included in this review. One article reported drug levels of nivolumab in CSF. Intracranial responses were achieved in 16 of 35 patients (46%; 95% confidence interval (CI) 29-63) in a phase II study cohort treated with nivolumab and ipilimumab. In a second phase II study in 94 patients, the rate of intracranial clinical benefit was 57% (95% CI 47-68). The CSF/serum ratio of nivolumab was 0.88-1.9% in a cohort of metastatic melanoma patients treated with nivolumab 1-3 mg/kg. Nivolumab concentrations ranged from 35 to 150 ng/ml in CSF of these patients, which is in the range of the half maximal effective concentration (EC50) of 0.64 nM. CONCLUSIONS: Ipilimumab and nivolumab are active in melanoma brain metastases. Nivolumab penetrates into the CSF. Based on the described findings the general consensus that monoclonal antibodies do not penetrate into the central nervous system (CNS) and cannot have a direct intracranial effect needs to be reconsidered.


Assuntos
Antineoplásicos Imunológicos/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Ipilimumab/líquido cefalorraquidiano , Melanoma/tratamento farmacológico , Nivolumabe/líquido cefalorraquidiano , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/sangue , Neoplasias Encefálicas/secundário , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/sangue , Melanoma/secundário , Nivolumabe/administração & dosagem , Nivolumabe/sangue
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