pazopanib and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

The incidence and mortality from renal cell cancer (RCC) is increasing. RCC tumors are particularly vascular in nature as a result of disruption of the VHL gene and/or its upstream pathway leading to upregulation of the hypoxia-inducible factor transcription factor. The hypoxia-inducible factor pathway drives angiogenesis by upregulating VEGF and bFGF, amongst other proangiogenic downstream target genes. Therapies which target angiogenesis have been successful in treating metastatic RCC (mRCC) and the receptor tyrosine kinase inhibitor, pazopanib, is licensed for first line treatment of mRCC. This review details the past, current and future roles of pazopanib in the treatment of mRCC.

Topics: Angiogenesis Inhibitors; Animals; Biomarkers, Tumor; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides

Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Liver; Male; Middle Aged; Neoplasms; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Young Adult

Tyrosine kinase inhibitors (TKIs) represent important therapeutic alternatives to, or combinations with, traditional cytotoxic chemotherapy. Despite their selective molecular targeting and demonstrated clinical benefit, TKIs produce a range of serious adverse events, including drug-induced liver injury, that require careful patient management to maintain treatment benefit without harm. Genetic characterization of serious adverse events can identify mechanisms of injury and improve safety risk management. This review presents pharmacogenetic comparisons of two approved TKIs, lapatinib and pazopanib, which reveal different mechanisms of injury and inform the characteristics and risk of serious liver injury in treated patients. The data presented demonstrate the utility of genetic studies to investigate drug-induced liver injury and potentially support its management in patients.

Topics: Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Gilbert Disease; Glucuronosyltransferase; Humans; Indazoles; Lapatinib; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Sulfonamides

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m for the first dose and 320 mg/m every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in γ-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Early Termination of Clinical Trials; Humans; Indazoles; Male; Neutropenia; Organoplatinum Compounds; Palliative Care; Prospective Studies; Pyrimidines; Salvage Therapy; Sulfonamides; Thrombocytopenia; Urologic Neoplasms; Vinblastine

Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the bile salt export pump (BSEP) is one mechanism of DILI. Dasatinib, pazopanib, and sorafenib are tyrosine kinase inhibitors (TKIs) that competitively inhibit BSEP and increase serum biomarkers for hepatotoxicity in ∼25-50% of patients. However, the mechanism(s) of hepatotoxicity beyond competitive inhibition of BSEP are poorly understood. This study examined mechanisms of TKI-mediated hepatotoxicity associated with altered bile acid homeostasis. Dasatinib, pazopanib, and sorafenib showed bile acid-dependent toxicity at clinically relevant concentrations, based on the C-DILI assay using sandwich-cultured human hepatocytes (SCHH). Among several bile acid-relevant genes, cytochrome P450 (CYP) 7A1 mRNA was specifically upregulated by 6.2- to 7.8-fold (dasatinib) and 5.7- to 9.3-fold (pazopanib), compared with control, within 8 hours. This was consistent with increased total bile acid concentrations in culture medium up to 2.3-fold, and in SCHH up to 1.4-fold, compared with control, within 24 hours. Additionally, protein abundance of sodium taurocholate co-transporting polypeptide (NTCP) was increased up to 2.0-fold by these three TKIs. The increase in NTCP protein abundance correlated with increased function; dasatinib and pazopanib increased hepatocyte uptake clearance (CL

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 11; Bile Acids and Salts; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cholesterol 7-alpha-Hydroxylase; Dasatinib; Hepatocytes; Humans; Indazoles; Organic Anion Transporters, Sodium-Dependent; Protein Kinase Inhibitors; Pyrimidines; Sorafenib; Sulfonamides; Symporters

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Painkillers and fever antipyretics are the most common cause of DILI. Hepatic injury can be provoked by DILI as hepatocellular or cholestatic type.. A 48-year-old woman presented jaundice accompanied by nausea and vomiting. The patient was an inactive hepatitis B carrier with low viral titer and was diagnosed renal cell carcinoma (RCC) with hepatic metastasis requiring pazopanib treatment. Prior to administration of pazopanib, tenofovir administration was started to prevent exacerbation of hepatitis B. The patient was referred to clinic of gastroenterology department due to sudden elevation of bilirubin after 5 weeks of pazopanib treatment.. Abdominal ultrasound and computed tomography showed non-specific finding other than metastatic nodule in the liver and liver cirrhosis. After then, the patient was performed liver biopsy, and the biopsy result was acute cholestatic hepatitis with centrilobular area necrosis and portal inflammation. Therefore, considering the clinical history and biopsy results, the patient was diagnosed as DILI due to pazopanib.. After the biopsy, empirical steroid therapy was initiated and after 7 weeks of pazopanib discontinuation.. The total bilirubin level returned to normal from peak level of 24.61 to 1.52 mg/dL.. In patients with renal cell carcinoma, pazopanib treatment requires clinical caution as it causes rare complications such as severe jaundice and acute cholestatic hepatitis.

Topics: Bilirubin; Biopsy; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Female; Hepatitis B; Humans; Indazoles; Jaundice; Kidney Neoplasms; Middle Aged; Nausea; Pyrimidines; Steroids; Sulfonamides; Tomography, X-Ray Computed; Ultrasonography; United States; Vomiting

Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various degrees of hepatotoxicity. Our study aimed to investigate the effect of taxifolin on pazopanib-induced liver toxicity. A total of 18 rats were divided into three groups: the pazopanib (PP), pazopanib plus taxifolin (TPP), and control (C) group. Taxifolin was administered to the TPP (n=6) group with a dose of 50 mg/kg. Distilled water was orally admnistered to the C (n=6) and PP (n=6) groups as a solvent. Subsequently, pazopanib 200 mg/kg was administered to the TPP and PP groups via the stomach. This procedure was repeated once a day for four weeks. Then, all rats were sacrificed, and their livers were removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), and total antioxidant status (TAS) levels were evaluated. MDA and TOS levels were higher in the PP group compared with the levels of the other parameters (P<0.001). tGSH and TAS levels were lower in the PP group than in the TPP and C groups (P<0.001), and the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were higher. Furthermore, liver tissue damage, including hemorrhage, hydropic degeneration, and necrosis was observed in the PP group. Administration of taxifolin before pazopanib significantly improved degenerative changes. Our study demonstrated that the administration of taxifolin is significantly effective in preventing pazopanib-induced hepatotoxicity in rats.

Topics: Animals; Chemical and Drug Induced Liver Injury; Indazoles; Liver; Male; Protective Agents; Pyrimidines; Quercetin; Rats; Rats, Wistar; Sulfonamides

Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes.. Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods.. Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P = .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P = .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism.. UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanib-induced liver toxicity in patients with mRCC.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glucuronosyltransferase; Humans; Indazoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Function Tests; Longitudinal Studies; Male; Middle Aged; Polymorphism, Genetic; Progression-Free Survival; Prospective Studies; Pyrimidines; Retrospective Studies; Sulfonamides

Pazopanib, a tyrosine kinase inhibitor, has been a standard first-line treatment for metastatic renal cell carcinoma (mRCC). Recent trials combining pazopanib with programmed cell death protein 1 (PD-1) inhibitors, including pembrolizumab, have shown excessive hepatotoxicity. We report a case of fatal hepatotoxicity from vanishing bile duct syndrome (VBDS) associated with pazopanib treatment, in a patient previously exposed to pembrolizumab. This is the first report of pazopanib-induced VBDS. We postulate whether prior exposure to pembrolizumab predisposed towards pazopanib-induction of VBDS, and discuss potential risks of sequential PD-1 inhibitor followed by pazopanib in mRCC, due to prolonged half-lives of PD-1 inhibitors.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Bile Duct Diseases; Bile Ducts, Intrahepatic; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides; Syndrome

Nomograms have been developed for the prediction of progression-free survival (PFS) and liver toxicity in patients with advanced renal cell carcinoma (RCC) who are treated with pazopanib. The objectives of this study were to review clinical outcomes, to perform an external validation of these nomograms and to develop a new nomogram in Japanese patients.. A retrospective chart review of 150 Japanese patients with advanced RCC who received pazopanib at Kobe University Hospital and affiliated hospitals from March 2014 to June 2017 was performed. We evaluated the clinical efficacy and safety of pazopanib using logistic regression analysis to analyze the prognostic factors for overall survival (OS) and PFS. For nomogram validation, concordance index (C-index) and calibration were used.. The median PFS and OS in this study was 13.1 and 37.4 months, respectively. Multivariate analyses identified prognostic factors for OS (number of metastasis, white blood cell (WBC) count and lactate dehydrogenase) and PFS (number of metastasis, WBC count). The C-index of nomograms for 12-month PFS was 0.598. The C-index of nomograms for liver toxicity was 0.558. A new Nomogram for predicting 12-month PFS for patients who received pazopanib was developed and performed internal validation. The C-index of the nomogram was 0.768.. The clinical effect and safety of pazopanib reported in this study was similar to previous studies. This study suggests careful application of nomograms to Japanese patients treated with pazopanib. We have developed a new nomogram for predicting 12-month PFS with pazopanib therapy from Japanese patients.

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Nomograms; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Survival Rate

Pazopanib is an oral tyrosine kinase inhibitor registered for metastatic renal cell carcinoma and soft tissue sarcoma. Liver toxicity is a common side effect for this class of agents. The current opinion is that in case of severe liver toxicity pazopanib should be interrupted and restarted at a lower dose after returning to Common Terminology Criteria for Adverse Events (CTCAE) grade 1. After recurrence of liver toxicity at the lower dose it is advised to permanently stop pazopanib. We describe a patient with an YWHAE-FAM22 translocated endometrial stromal sarcoma with a remarkable response to pazopanib despite recurrent liver toxicity.. A 40 year old woman was diagnosed with metastatic YWHAE-FAM22 translocated endometrial stromal sarcoma. She was treated successively with doxorubicin, megestrol acetate and anastrozole, before pazopanib was initiated. Several dose interruptions and reductions were necessary due to liver toxicity, but nevertheless she had a good partial response. Seven months after the start, pazopanib was permanently stopped because of a bilateral pneumothorax. Nine months later it was reinitiated because of progression and was continued for another 8 months until final disease progression.. In contrast to the current summary of product characteristics of pazopanib, the drug was successfully continued despite recurrent liver toxicity, and no further liver function deterioration was found. This case suggests that further dose reductions are good practice when liver toxicity limits treatment in responding patients. Secondly, this patient with rare YWHAE-FAM22 translocated endometrial stromal sarcoma showed a remarkable response to VEGFR/KIT inhibitor pazopanib. Recently, it was reported that this specific subtype of endometrial stromal sarcoma overexpresses CD117, but has no KIT mutations. This case illustrates that (a) pazopanib can be continued in patients with recurrent liver toxicity after dose reductions under strict surveillance and that (b) pazopanib shows good efficacy in YWHAE-FAM22 translocated endometrial stromal sarcoma.

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indazoles; Liver; Neoplasm Recurrence, Local; Pyrimidines; Sarcoma, Endometrial Stromal; Sulfonamides

Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity.

Topics: Administration, Oral; Alkaline Phosphatase; Animals; Bilirubin; Blood Chemical Analysis; Blood Glucose; Chemical and Drug Induced Liver Injury; Fatty Liver; Hemosiderin; Indazoles; Kupffer Cells; Liver; Male; Pyrimidines; Rats; Rats, Wistar; Sulfonamides

Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare  putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.

Topics: Aldehydes; Amines; Catalysis; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Humans; Indazoles; Metalloporphyrins; Microsomes, Liver; Oxidation-Reduction; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides; Sunitinib

Topics: Adult; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Heart Failure; Humans; Indazoles; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Pazopanib is a potent and selective multi-targeted tyrosine kinase inhibitor that has been reported to extend progression-free survival in cases of metastatic soft-tissue sarcoma. However, the efficacy of pazopanib for cutaneous angiosarcoma has not been confirmed. We report eight cases of angiosarcoma treated with pazopanib, and review the efficacy and safety of pazopanib therapy. We retrospectively investigated the clinical information, including age, sex, body surface area, location, performance status, lung or pleural metastasis, preceding treatment, oral dose of pazopanib, response rate, progression-free survival and adverse effects. Five of the eight patients needed to stop the pazopanib treatment due to severe adverse effects, including thrombocytopenia, anemia, drug-associated pancreatitis, acute fulminant hepatitis and general fatigue. Progression-free survival ranged 0.5-3.5 months (mean ± standard deviation, 1.81 ± 1.03). Overall survival ranged 3-26 months (14.13 ± 9.47). Six of the eight cases showed progressive disease, and two of the eight cases showed stable disease. To assess overall survival in angiosarcoma treated with pazopanib, we compared the pazopanib-treated group (n = 8) with the non-pazopanib-treated control group (n = 10). There was no significant difference between two groups (P = 0.19, log-rank test). In conclusion, our case series suggests that pazopanib does not bring remarkable improvement in patients with angiosarcoma.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anemia; Chemical and Drug Induced Liver Injury; Disease-Free Survival; Fatigue; Female; Hemangiosarcoma; Humans; Indazoles; Male; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Retrospective Studies; Sulfonamides; Thrombocytopenia; Treatment Outcome

Idiosyncratic drug-induced hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing.

Topics: Acetaminophen; Cell Differentiation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A2; Gene Expression Regulation; Glutathione; Hepatocytes; Humans; Indazoles; Induced Pluripotent Stem Cells; Iron; Organ Specificity; Oxidative Stress; Principal Component Analysis; Pyrimidines; Reactive Oxygen Species; RNA, Messenger; Sulfonamides; Transcription, Genetic

Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.. The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.. The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.. These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Female; Genetic Predisposition to Disease; Heterozygote; HLA-B Antigens; Humans; Indazoles; Liver Function Tests; Male; Middle Aged; Models, Molecular; Molecular Conformation; Neoplasms; Pyrimidines; Structure-Activity Relationship; Sulfonamides; Young Adult

Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data.. Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.. The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.. There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Chemical and Drug Induced Liver Injury; Disease-Free Survival; Female; Fibrosarcoma; Humans; Hypertension; Indazoles; Japan; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Neurilemmoma; Pneumothorax; Product Surveillance, Postmarketing; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Sulfonamides; Survival Analysis; Thrombocytopenia

To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients.. A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists.. In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib.. Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Topics: Aged; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Cohort Studies; Computer Communication Networks; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisolone; Pyrimidines; Salvage Therapy; Sarcoma, Synovial; Sulfonamides

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Novel drugs targeting molecular pathways involved in tumor development have revolutionized cancer treatment. Radiologists often focus on therapeutic response when evaluating cancer patients and may miss important signs of drug toxicity. This article familiarizes radiologists with the complications of molecular targeted agents in abdominal solid organs, enabling early identification and appropriate intervention and thus reducing patient morbidity and mortality.. Knowledge of the common abdominal toxicities--including hepatitis, cholecystitis, pancreatitis, fluid retention, and infection--is crucial for early diagnosis, which may spare patients devastating complications or the need for surgery.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Chemical and Drug Induced Liver Injury; Cholecystitis; Early Diagnosis; Edema; Fatty Liver; Female; Health Knowledge, Attitudes, Practice; Humans; Indazoles; Infections; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms; Pancreatitis; Protein-Tyrosine Kinases; Pyrimidines; Radiography, Abdominal; Sulfonamides; Vascular Endothelial Growth Factor A; Young Adult

Topics: Aged; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Vascular Endothelial Growth Factor A

Topics: Alanine Transaminase; Anticholesteremic Agents; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Interactions; Humans; Hypercholesterolemia; Incidence; Indazoles; Neoplasm Proteins; Neoplasms; Polymorphism, Single Nucleotide; Pyrimidines; Reference Values; Simvastatin; Sulfonamides

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests