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In Vivo (Athens, Greece) 2024Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension.
BACKGROUND/AIM
Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension.
PATIENTS AND METHODS
In total, 47 patients who started pazopanib treatment for renal cell carcinoma or soft tissue sarcoma during hospitalization at Kurume University Hospital from November 2012 to February 2020 were included in the study. Patient background factors associated with pazopanib-induced hypertension were analyzed using a logistic regression model. Subsequently, a time-dependent receiver operating characteristic (ROC) analysis was performed to evaluate changes in the predictive performance of predictors of pazopanib-induced hypertension over time.
RESULTS
Logistic regression analysis showed that total bilirubin (t-bil) and sex are predictors of pazopanib-induced hypertension, along with systolic blood pressure (SBP) before pazopanib introduction. Additionally, evaluation of area under the curve (AUC) changes over time during the first 20 days of pazopanib treatment using time-dependent ROC showed that the AUC tended to be higher in the first half for SBP and in the second half for t-bil. Moreover, models including these two factors (SBP+t-bil and SBP+t-bil+sex) maintained a higher AUC from the early to late stages of the treatment period.
CONCLUSION
Total bilirubin and sex can serve as predictors of pazopanib-induced hypertension. Total bilirubin may contribute to the prediction of the development of hypertension after day 5.
Topics: Indazoles; Humans; Pyrimidines; Male; Female; Hypertension; Sulfonamides; Middle Aged; Aged; ROC Curve; Angiogenesis Inhibitors; Adult; Carcinoma, Renal Cell; Risk Factors; Blood Pressure; Aged, 80 and over; Kidney Neoplasms; Prognosis
PubMed: 38936947
DOI: 10.21873/invivo.13643 -
Clinical Genitourinary Cancer Apr 2019Severe adverse events frequently occur in patients treated with pazopanib, necessitating dose reduction and discontinuation. However, information on the...
BACKGROUND
Severe adverse events frequently occur in patients treated with pazopanib, necessitating dose reduction and discontinuation. However, information on the exposure-toxicity relationship is limited.
PATIENTS AND METHODS
For this retrospective and observational clinical study, we examined 27 patients with renal cell carcinoma treated with pazopanib and enrolled between October 2014 and March 2018. The primary goal was to evaluate the association between trough pazopanib concentration and occurrence of grade ≥ 3 toxicities, and secondarily, to estimate the association between trough pazopanib concentration and objective response rate.
RESULTS
Mean trough pazopanib concentration was significantly higher in the grade ≥ 3 toxicity group (n = 9) than in the grade ≤ 2 toxicity group (n = 18). Based on the receiver operating characteristic curve, the threshold value of trough pazopanib concentration for predicting grade ≥ 3 toxicities was 50.3 μg/mL (area under the curve, 0.85; 95% confidence interval, 0.70-0.99; P < .05). In the pazopanib < 20.5 μg/mL group (n = 3), no patient experienced an objective response. Objective response rates between patients with 20.5 to 50.3 μg/mL pazopanib (n = 11) and patients with ≥ 50.3 μg/mL (n = 13) were similar (45.5% vs. 46.2%).
CONCLUSION
From results of this study, the target trough pazopanib concentration range may be 20.5 to 50.3 μg/mL for patients with renal cell carcinoma.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; ROC Curve; Retrospective Studies; Sulfonamides; Survival Analysis; Treatment Outcome
PubMed: 30598361
DOI: 10.1016/j.clgc.2018.12.001 -
Pazopanib: Evidence review and clinical practice in the management of advanced renal cell carcinoma.BMC Pharmacology & Toxicology Nov 2018Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics...
BACKGROUND
Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice.
METHODS
A non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer.
RESULTS
The efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all.
CONCLUSIONS
This paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Quality of Life; Sulfonamides; Treatment Outcome
PubMed: 30477570
DOI: 10.1186/s40360-018-0264-8 -
JAMA Oncology Apr 2017To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal... (Randomized Controlled Trial)
Randomized Controlled Trial
Alternating Treatment With Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients With Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial.
IMPORTANCE
To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma.
OBJECTIVE
To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib.
DESIGN, SETTING, AND PARTICIPANTS
This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year.
INTERVENTIONS
First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm).
MAIN OUTCOME AND MEASURES
The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life.
RESULTS
A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed.
CONCLUSIONS AND RELEVANCE
Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01408004.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Everolimus; Female; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Quality of Life; Sulfonamides
PubMed: 27918762
DOI: 10.1001/jamaoncol.2016.5202 -
International Journal of Cancer Jan 2015Fatigue is the most common symptom associated with cancer and cancer treatment. We performed an up-to-date meta-analysis to determine the incidence and relative risk... (Meta-Analysis)
Meta-Analysis Review
Fatigue is the most common symptom associated with cancer and cancer treatment. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) of fatigue in patients (pts) with cancer treated with sorafenib (SO), sunitinib (SU) and pazopanib (PZ). PubMed databases were searched for articles published till August 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. Fifteen studies were included in our analysis. A total of 6,996 pts was enrolled: 2,260 had renal cell carcinomas (RCC), 1,691 non-small cell lung cancers, 1,290 breast cancers, 823 hepatocellular carcinomas, 362 soft tissue sarcomas, 304 gastrointestinal solid tumors, 165 neuroendocrine tumors and 101 melanomas. When stratified by drug, SO registered lower incidence and RR of all and high-grade fatigue when compared to SU, whereas the difference between SO and PZ was significant only for all-grade fatigue (p < 0.001). The difference between SU and PZ was significant for high-grade (p < 0.001) but not for all-grade fatigue (p = 0.52). In RCC pts, PZ showed the lower incidence and RR of all and high-grade fatigue. The differences were significant for SU vs. SO (p < 0.001), SU vs. PZ (p < 0.001) and SO vs. PZ (p < 0.001). Treatment with SO, SU and PZ is associated with an increased incidence of fatigue in pts with cancer. Early and appropriate management is required to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Fatigue; Humans; Incidence; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Risk; Sorafenib; Sulfonamides; Sunitinib
PubMed: 24415642
DOI: 10.1002/ijc.28715 -
International Journal of Molecular... Jun 2024The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper...
The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.
Topics: Humans; Drug Resistance, Neoplasm; Kidney Neoplasms; Protein Kinase Inhibitors; Cell Line, Tumor; Sunitinib; Sulfonamides; Metabolomics; Indazoles; Carcinoma, Renal Cell; Pyrimidines; Metabolome; Cell Proliferation; Tyrosine Kinase Inhibitors
PubMed: 38928035
DOI: 10.3390/ijms25126328 -
Pharmacology Research & Perspectives Jun 2019Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)...
Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.
Topics: Animals; Arterial Pressure; Disease Models, Animal; Drug Administration Schedule; Humans; Hypertension; Indazoles; Male; Piperidines; Pyrimidines; Quinazolines; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfonamides
PubMed: 31164986
DOI: 10.1002/prp2.477 -
American Journal of Clinical Oncology Jun 2016Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule...
OBJECTIVES
Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors.
METHODS
Dose escalation started at 32 mg/m of ixabepilone and increased to 40 mg/m. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines.
RESULTS
Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival.
CONCLUSIONS
The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytokines; Disease-Free Survival; E-Selectin; Epothilones; Fatigue; Female; Humans; Indazoles; Male; Middle Aged; Neoplasms; Neutropenia; Pyrimidines; Retreatment; Sulfonamides; Survival Rate; Thrombocytopenia
PubMed: 24577167
DOI: 10.1097/COC.0000000000000053 -
Biological & Pharmaceutical Bulletin 2023Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment...
Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist-urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26-0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47-9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.
Topics: Humans; Carcinoma, Renal Cell; Pharmacists; Urologists; Kidney Neoplasms; Retrospective Studies; Treatment Outcome; Indazoles; Angiogenesis Inhibitors
PubMed: 37532558
DOI: 10.1248/bpb.b22-00917 -
Journal of Clinical Oncology : Official... Apr 2023
Topics: Humans; Sunitinib; Carcinoma, Renal Cell; Interferon-alpha; Kidney Neoplasms; Indazoles; Pyrroles; Antineoplastic Agents
PubMed: 37018918
DOI: 10.1200/JCO.23.00153