2604 Liver toxicity associated with the use of Pazopanib in renal cancer patients: UK teaching hospital experience

Jain, Ankit; Canipari, Cinzia; Haque, Farzana; Solanki, Hina; Kumar, Amit; Porfiri, Emilio

doi:10.1016/s0959-8049(16)31422-8

Cited by 3 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Аномальные тесты функции печени (например, повы-шение AЛT, AСT или билирубина) имели место у 13-36% пациентов; 3-4-я степень токсичности -у ≤15,7% паци-ентов [19][20][21][25][26]. Частота отмены препарата из-за побочных эффектов в разных исследованиях варьирова-ла от 6 до 15% [19][20][21][22]24].…”

Section: профиль безопасности и токсичностиunclassified

Pazopanib as first-line therapy for patients with metastatic kidney cancer

Алексеев¹,

Shevchuk²

2018

Med. sov.

View full text Add to dashboard Cite

Б.Я. АЛЕКСЕЕВ, д.м.н., профессор, И.М. ШЕВЧУК, к.м.н. Национальный медицинский исследовательский центр радиологии Минздрава России, Москва ПАЗОПАНИБ -ПРЕПАРАТ ПЕРВОЙ ЛИНИИ ТЕРАПИИ У БОЛЬНЫХ С МЕТАСТАТИЧЕСКИМ РАКОМ ПОЧКИ Пазопаниб (Вотриент®) -пероральный низкомолекулярный мультикиназный ингибитор, который в первую очередь инги-бирует рецептор 1, 2 и 3 сосудистого эндотелиального фактора роста, рецепторы α и β тромбоцитарного фактора роста эндотелия и рецепторы c-kit-фактора стволовых клеток. В предварительных экспериментах с использованием моделей ангиогенеза у мышей и кроликов пазопаниб ингибировал ангиогенез, вызванный комбинированным фактором роста эндо-телия сосудов и основным фактором роста фибробластов. Хотя препарат был разработан как терапевтический мультиопу-холевый агент, в настоящее время во многих странах он одобрен для применения при распространенной саркоме мягких тканей и почечно-клеточном раке (ПКР). В мультицентровых рандомизированных исследованиях по изучению эффектив-ности пазопаниба в качестве препарата первой линии у больных с метастатическим ПКР он продемонстрировал значитель-но лучшую безрецидивную выживаемость (БРВ) по сравнению с цитокиновой терапией и одинаковое время до прогресси-рования в случае применения сунитиниба. Кроме того, побочные эффекты, такие как нарушение функции печени и артери-альная гипертензия, как правило, управляемы, и с точки зрения качества жизни и экономической эффективности пазопаниб представляется более предпочтительным агентом по сравнению с другими альтернативными препаратами. Ключевые слова: метастатический почечно-клеточный рак, мультитаргетные ингибиторы тирозинкиназ, пазопаниб. B.Ya. ALEKSEEV, I.M. SHEVCHUK National Medical Research Radiological Center of the Ministry of Health of Russia, Moscow PAZOPANIB AS FIRST-LINE THERAPY FOR PATIENTS WITH METASTATIC KIDNEY CANCER Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that predominantly inhibits vascular endothelial growthfactor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β and the stem cell factor receptor c-Kit. In preliminary experiments using mouse and rabbit models of angiogenesis, pazopanib inhibited angiogenesis caused by a combined vascular endothelial growth factor and a major fibroblast growth factor. Although the drug was developed as a therapeutic multi-tumour agent, it is currently approved in many countries for the treatment of advanced soft tissue sarcoma and renal cell carcinoma (RCC). In multicentre, randomized trials of the efficacy of pazopanib as a first-line therapy in patients with metastatic RCC, progression-free survival (PFS) was significantly greater in pazopanib recipients than in cytokine recipients and pazopanib was noninferior to sunitinib with respect to time to disease progression. In addition, side effects such as liver dysfunction and hypertension can be usually managed, and pazopanib is likely to be a more preferred cost-effective option and shows better quality-of-life compared to other alternative drugs.

show abstract

Section: профиль безопасности и токсичностиunclassified

Pazopanib as first-line therapy for patients with metastatic kidney cancer

Алексеев¹,

Shevchuk²

2018

Med. sov.

View full text Add to dashboard Cite

show abstract

Pazopanib: a Review in Advanced Renal Cell Carcinoma

Frampton

2017

Targ Oncol

View full text Add to dashboard Cite

Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naïve and cytokine-pretreated patients and, as a first-line therapy, was noninferior to intermittent sunitinib with respect to PFS. However, pazopanib had a tolerability profile that was distinguishable from that of sunitinib, based on lower incidences of most adverse events, particularly those associated with discomfort, such as fatigue, hand-foot syndrome and stomatitis. Consistent with this, health-related quality of life (HR-QOL) measures evaluating fatigue, hand/foot soreness and mouth/throat soreness significantly favoured pazopanib over sunitinib. In addition, significantly more patients expressed a preference for pazopanib over sunitinib, primarily because of better overall HR-QOL and less fatigue. Efficacy and tolerability findings from these prospective clinical trials have been substantiated by evidence from a number of retrospective studies evaluating unselected real-world patients with metastatic RCC who received pazopanib (or sunitinib) as a first-line therapy. Thus, data from clinical trials supplemented with that from clinical practice support the use of pazopanib as a standard or alternative first-line treatment for advanced or metastatic RCC.

show abstract

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

Wang

Yang

Liang³

et al. 2018

Xenobiotica

View full text Add to dashboard Cite

To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.

show abstract

2604 Liver toxicity associated with the use of Pazopanib in renal cancer patients: UK teaching hospital experience

Cited by 3 publications

References 0 publications

Pazopanib as first-line therapy for patients with metastatic kidney cancer

Pazopanib as first-line therapy for patients with metastatic kidney cancer

Pazopanib: a Review in Advanced Renal Cell Carcinoma

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

Contact Info

Product

Resources

About