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Current Opinion in Urology Sep 2015In patients with metastatic renal cell carcinoma and favourable or intermediate risk, sunitinib, pazopanib, and bevacizumab along with interferon have been recommended... (Review)
Review
PURPOSE OF REVIEW
In patients with metastatic renal cell carcinoma and favourable or intermediate risk, sunitinib, pazopanib, and bevacizumab along with interferon have been recommended with identical evidence level I, recommendation grade A. In clinical practice, most physicians and patients are likely to favour an oral treatment (i.e., sunitinib or pazopanib). Choosing between those two tyrosine kinase inhibitors may prove challenging. Two randomized trials have been conducted to facilitate treatment choices, COMPARZ, and PISCES. We discuss below the design of these trials, their results, their potential interpretation, and their clinical implications for selecting treatment.
RECENT FINDINGS
Both trials were reported to meet the primary endpoint (i.e., noninferiority of pazopanib versus sunitinib) and patient's preference of pazopanib over sunitinib. However, several methodological aspects have raised doubts about the reliability of these conclusions. Pitfalls include the patients selected for the final analysis, discrepancies of results between the per protocol and intention-to-treat populations, the time points at which quality of life and disease were assessed.
SUMMARY
A rigorous head-to-head comparison of pazopanib versus sunitinib is yet to be performed. Clinical considerations and physicans' experience, rather than the reported results of these trials, may continue to influence treatment choices.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Patient Selection; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Sulfonamides; Sunitinib; Time Factors; Treatment Outcome
PubMed: 26148069
DOI: 10.1097/MOU.0000000000000207 -
Frontiers in Endocrinology 2023In recent years, the potential toxicities of different pharmaceuticals toward the thyroid system have received increasing attention. In this study, we aim to evaluate...
INTRODUCTION
In recent years, the potential toxicities of different pharmaceuticals toward the thyroid system have received increasing attention. In this study, we aim to evaluate the toxic effects of pazopanib and axitinib, two anti-tumor drugs with widespread clinical use, on thyroid function in the zebrafish model.
METHODS
We measured levels of thyroid-related hormones using the commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit. Whole-mount in situ hybridization (WISH) analysis was employed to detect target gene expression changes. Morphology of the thyroid were evaluated by using transgenic Tg (: EGFP) fish line under a confocal microscope. The relative mRNA expression of key genes was verified through quantitative real-time polymerase chain reaction (RT‒qPCR). The size and number of the follicles was quantified whereby Hematoxylin-Eosin (H & E) staining under a light microscope.
RESULTS
The results revealed that fertilized zebrafish embryos were incubated in pazopanib or axitinib for 96 hours, development and survival were significantly affected, which was accompanied by significant disturbances in thyroid endocrine system (e.g., increased thyroid-stimulating hormone (TSH) content and decreased triiodothyronine (T3) and thyroxine (T4) content, as well as transcription changes of genes associated with the hypothalamus-pituitary-thyroid (HPT) axis. Moreover, based on whole-mount in situ hybridization staining of tg and histopathological examination of zebrafish embryos treated with pazopanib and axitinib, we observed a significantly abnormal development of thyroid follicles in the Tg (: EGFP) zebrafish transgenic line.
CONCLUSION
Collectively, these findings indicate that pazopanib and axitinib may have toxic effects on thyroid development and function, at least partially, by influencing the regulation of the HPT axis. Thus, we believe that the potential thyroid toxicities of pazopanib and axitinib in their clinical applications should receive greater attention.
Topics: Animals; Axitinib; Zebrafish; Thyroid Gland; Larva; Antineoplastic Agents; Animals, Genetically Modified
PubMed: 37600710
DOI: 10.3389/fendo.2023.1204678 -
Clinical Genitourinary Cancer Oct 2022Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability...
A Study of Pazopanib Safety and Efficacy in Patients With Advanced Clear Cell Renal Cell Carcinoma and ECOG Performance Status 2 (Pazo2): An Open label, Multicentre, Single Arm, Phase II Trial.
AIM
Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability and efficacy of pazopanib as first-line treatment in renal cancer patients with ECOG PS2.
METHODS
Pazo2 was a prospective, single arm, open label, multicentre, phase II trial, conducted in 26 UK centres. Eligible patients were aged ≥18 years, with advanced or metastatic renal cancer and a clear cell component (aRCC), measurable disease as per RECIST Criteria 1.1, and ECOG PS2. Co-primary outcomes, assessed at 6-months after patients entered the trial, were tolerability, defined as the proportion of patients who did not develop "intolerable" adverse events, and efficacy, defined as the proportion of all patients who were progression-free and alive.
RESULTS
Between February 21, 2013 and August 12, 2016, 75 patients were registered. Median age was 68.6 years (IQR 64.6-76.0), 100% ECOG PS2, 62.7% 'poor risk' (International Metastatic Renal-Cell Carcinoma Database Consortium). Of the 65 evaluable patients, 70.8% (95% CI: 58.8, 80.4) did not develop "intolerable" adverse events and 56.9% (95% CI: 44.8, 68.2) were still alive and progression-free 6 months after starting pazopanib. Twenty-seven patients developed serious adverse events deemed to be related to pazopanib.
CONCLUSION
These data suggests that pazopanib is tolerated and effective in aRCC patients with PS2 and represents a treatment option for patients who cannot receive or tolerate immune checkpoint inhibitors.
Topics: Adolescent; Adult; Aged; Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Indazoles; Kidney Neoplasms; Prospective Studies; Pyrimidines; Sulfonamides
PubMed: 35803859
DOI: 10.1016/j.clgc.2022.06.012 -
Clinical Pharmacology in Drug... Sep 2022This study aimed to evaluate the bioequivalence of two pazopanib tablet formulations in healthy Chinese subjects. A randomized, open-label, single-dose, two-period,... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence of two pazopanib tablet formulations in healthy Chinese subjects. A randomized, open-label, single-dose, two-period, two-sequence, crossover study was conducted under fasting conditions. A total of 32 eligible subjects were randomly administered a single dose of a 200-mg generic or branded pazopanib tablet with a 16-day washout period. Blood samples were collected before and up to 72 hours after dosing. Pharmacokinetic parameters were analyzed with noncompartmental analysis. Safety assessments included physical examinations, laboratory tests, and adverse events reporting. Maximum plasma concentration (C ), area under the plasma concentration-time curve (AUC) from zero to the last quantifiable concentration (AUC ), and AUC from zero to infinity (AUC ) were similar between the generic and branded products (all P > .05). The 90% confidence intervals of the geometric mean ratio of the test/reference products for C , AUC , and AUC were 89.1%-117.1%, 81.9%-108.5%, and 82.4%-109.6%, respectively. There were no serious adverse events during the study. The newly developed generic pazopanib tablet was bioequivalent to the reference product under fasting conditions. Both formulations were well tolerated in healthy Chinese volunteers.
Topics: Area Under Curve; Biological Availability; China; Cross-Over Studies; Drugs, Generic; Humans; Indazoles; Pyrimidines; Sulfonamides; Tablets; Therapeutic Equivalency
PubMed: 35384398
DOI: 10.1002/cpdd.1096 -
Scientific Reports Feb 2023The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough...
The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.
Topics: Humans; Carcinoma, Renal Cell; East Asian People; Sarcoma; Indazoles; Soft Tissue Neoplasms; Kidney Neoplasms; Angiogenesis Inhibitors
PubMed: 36746987
DOI: 10.1038/s41598-023-28688-9 -
Indian Journal of Cancer 2021In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is...
BACKGROUND
In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is important to explore the feasibility (toxicity, acceptance), efficacy (response rates, survival), and optimal dose requirement of pazopanib in M-STS in India.
METHODS
All patients who received pazopanib for M-STS in 2013-2018 in Tata Memorial Centre were included. Institutional ethics committee approval was obtained. Assessment for response with contrast computed tomography scans was done as per the response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Pazopanib was continued until progression or unacceptable toxicity. Clinical benefit rates and survival were evaluated by Kaplan-Meier method. All statistical calculations were done using SPSS version 21.0.
RESULTS
Seventy-two consecutive patients with a median follow-up of 17 (4-40) months were included in this study. Median lines of prior therapy were 2 (0-2). Among 50 evaluable patients, there were 12/50 (24%) partial responses, 25/50 (50%) stable disease, and 15/50 (30%) progressive disease. Median progression-free survival was 5 (95% confidence interval (CI) 3-6.9) months and median overall survival was 11 (95% CI 6.8-15.2) months. Adverse effects (G2/G3) in patients: hand foot syndrome-28%, hyperbilirubinemia/transaminitis-10%, diarrhea-20%, hypertension-17%, hypothyroidism-15%, anemia-6%, and fatigue-17%. Notably, 40% patient required dose reduction and median dose was 600 (200-800) mg daily.
CONCLUSION
Pazopanib was found a feasible treatment option for M-STS in India with internationally comparable outcomes. However, significant patients required dose modifications, and median tolerated dose was lower than the standard 800 mg dose. This novel finding merits confirmation in larger cohorts for reproducibility.
Topics: Adult; Aged; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis; Young Adult
PubMed: 33753596
DOI: 10.4103/ijc.IJC_314_19 -
Expert Opinion on Drug Metabolism &... Aug 2017Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of... (Review)
Review
Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy. Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS. Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.
Topics: Angiogenesis Inhibitors; Female; Humans; Indazoles; Leiomyosarcoma; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Uterine Neoplasms
PubMed: 28678537
DOI: 10.1080/17425255.2017.1351943 -
Chemical Research in Toxicology Jan 2020Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require...
Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
Topics: Aldehydes; Angiogenesis Inhibitors; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Indazoles; Microsomes, Liver; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrimidines; Recombinant Proteins; Serum Albumin, Human; Sulfonamides; Sunitinib
PubMed: 31535851
DOI: 10.1021/acs.chemrestox.9b00205 -
Cancer Chemotherapy and Pharmacology Apr 2022The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The...
The effects of pazopanib on doxorubicin pharmacokinetics in children and adults with non-rhabdomyosarcoma soft tissue sarcoma: a report from Children's Oncology Group and NRG Oncology study ARST1321.
PURPOSE
The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported. As an exploratory aim, doxorubicin PK data were collected during the dose-finding phase of the study in patients receiving chemotherapy and pazopanib to assess the effect of pazopanib on doxorubicin PK parameters.
METHODS
Blood samples were collected during cycle 2 (week 4) of chemotherapy at the following time points from doxorubicin administration: predose, 5, 30, and 60 min, and 2, 4, 8, 24 ± 3, and 48 ± 3 h after dosing. The population pharmacokinetic and individual post hoc estimates of doxorubicin and doxorubicinol were determined by nonlinear mixed-effects modeling.
RESULTS
There were 52 doxorubicin and doxorubicinol samples from 7 individuals in this study (median age: 17 years; range 14-23). The doxorubicin clearance was 26.9 (16.1, 36.4, and 33.9) L/h/m (post hoc median and range) and 25.8 (23.3%) L/h/m [population estimate and IIV (CV%)]. The doxorubicinol apparent clearance was 67.5 (18.2, 1701) L/h/m (post hoc median and range) and 58.7 (63.7%) L/h/m [population estimate and IIV (CV%)].
CONCLUSION
The PK data of seven patients treated on ARST1321 is consistent with previously reported population and post hoc doxorubicin clearance and doxorubicinol apparent clearance estimates, showing that the addition of pazopanib does not significantly alter doxorubicin pharmacokinetics. These data support the safety of administration of pazopanib with doxorubicin-containing chemotherapy.
Topics: Adolescent; Adult; Child; Doxorubicin; Humans; Indazoles; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Young Adult
PubMed: 35083502
DOI: 10.1007/s00280-022-04397-4 -
Therapeutic Drug Monitoring Apr 2018Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by...
BACKGROUND
Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations.
METHODS
We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 → m/z 357 for pazopanib and m/z 442 → m/z 361 for the internal standard.
RESULTS
Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring.
CONCLUSIONS
In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib.
Topics: Ammonium Hydroxide; Angiogenesis Inhibitors; Biological Assay; Chromatography, Liquid; Drug Monitoring; Humans; Indazoles; Pyrimidines; Reproducibility of Results; Sulfonamides; Tandem Mass Spectrometry
PubMed: 29256969
DOI: 10.1097/FTD.0000000000000479