• Drug-drug interactions
• Kinase inhibitor
• Selpercatinib
• UDP-glucuronosyltransferase

• Axitinib
• Hepatotoxicity
• Pazopanib
• Pharmacogenomics
• Renal cell carcinoma

• Humans
• Carcinoma, Renal Cell/drug therapy
• Carcinoma, Renal Cell/genetics
• Glucuronosyltransferase/genetics
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/genetics
• Kidney Neoplasms/pathology
• Male
• Female
• Middle Aged
• Hyperbilirubinemia/chemically induced
• Hyperbilirubinemia/genetics
• Pyridines/therapeutic use
• Pyridines/adverse effects
• Anilides/therapeutic use
• Anilides/adverse effects
• Sulfonamides/adverse effects
• Sulfonamides/therapeutic use
• Indazoles/therapeutic use
• Aged
• Pyrimidines/therapeutic use
• Pyrimidines/adverse effects
• Axitinib/therapeutic use
• Axitinib/adverse effects
• Axitinib/administration & dosage
• Bilirubin/blood
• Genotype
• Adult
• Polymorphism, Genetic
• Aged, 80 and over

• Indazoles/therapeutic use
• Humans
• Sulfonamides/therapeutic use
• Sulfonamides/pharmacokinetics
• Pyrimidines/therapeutic use
• Pyrimidines/pharmacokinetics
• Drug Monitoring/methods
• Carcinoma, Renal Cell/drug therapy
• Sarcoma/drug therapy
• Kidney Neoplasms/drug therapy
• Angiogenesis Inhibitors/therapeutic use
• Angiogenesis Inhibitors/pharmacokinetics

• Children
• Concentration to dose ratio
• Epilepsy
• Genetic polymorphisms
• Pharmacogenomics
• Topiramate
• rs4148324

• Child
• Humans
• Anticonvulsants
• Epilepsy/drug therapy
• Epilepsy/genetics
• Polymorphism, Single Nucleotide/genetics
• Topiramate/therapeutic use

• drug prescription
• drug-related adverse events
• genetic variants
• pharmacogenomics
• pharmacokinetics

• cardiology
• oncology
• pathogenesis
• gastrointestinal diseases

• Humans
• Tyrosine Kinase Inhibitors
• Protein Kinase Inhibitors/adverse effects
• Protein-Tyrosine Kinases
• Carcinoma, Non-Small-Cell Lung/pathology
• Drug-Related Side Effects and Adverse Reactions/drug therapy
• Lung Neoplasms/pathology

• R01 HL150266 NHLBI NIH HHS
• R01 HL152090 NHLBI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

• cancer
• chemotherapy
• oncology
• personalized medicine
• pharmacogenomics

• Germ Cells
• Humans
• Medical Oncology
• Neoplasms/drug therapy
• Neoplasms/genetics
• Pharmacogenetics
• Quality of Life

• T32 GM007019 NIGMS NIH HHS

Sunitinib and pazopanib are both oral small molecule multityrosine kinase inhibitors (MTKI) used in the treatment of renal cell carcinoma (RCC). Hepatotoxicity or “liver injury” is the most important adverse effect of pazopanib administration, but little is known about the underlying mechanism. Liver injury may also occur in patients treated with sunitinib, but severe toxicity is extremely rare. Herein we report two new cases of severe liver injury induced by MTKI. Both cases are unique and exceptional. We assessed both cases for drug-induced liver injury (DILI) using the updated score Roussel Uclaf causality assessment method (RUCAM). The literature on potential pathogenic mechanisms and precautionary measures is reviewed.

A case of a metastatic RCC (mRCC) patient treated with pazopanib who had manifestation of severe liver injury is presented. These manifestations consisted of grade 4 alanine aminotransferase (ALT) increase and grade 4 hyperbilirubinemia. Alternate causes of acute or chronic liver disease were excluded. The patient gradually recovered from the liver injury and refused any further therapy for mRCC. The patient was diagnosed with acute myeloid leukemia (AML) two years later and eventually succumbed to the disease. The second case describes a mRCC patient treated with sunitinib for 3,5 years and fatal liver failure after 2 weeks of clarithromycin co-medication for acute bronchitis.

Liver injury has been commonly observed in TKI-treated patients with unpredictable course. Management requires regular routine liver enzyme-monitoring and the collaboration of medical oncologist and hepatologist. There is an unmet medical need for a risk stratification and definition of predictive biomarkers to identify potential genetic polymorphisms or other factors associated with TKI-induced liver injury. Any potential unrecommended concomitant therapy has to be avoided.

• Cancer
• Chemotherapy
• Efficacy
• Pharmacogenomics
• Targeted therapies
• Toxicity

• Antineoplastic Agents/therapeutic use
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Pharmacogenetics

• NIR fluorescent probes
• UDP-glucuronosyltransferase 1A1
• fluorescence imaging
• molecular-splicing strategy

Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.

To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).

Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).

Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (C_tau), 1.50-fold; AUC_tau, 1.41-fold; and C_max, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week C_tau, 1.24-fold; AUC_tau, 1.16-fold; and C_max, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10⁻⁵) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.

This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

• Gilbert’s syndrome
• UGT1A1
• belinostat
• cancer
• genotype
• irinotecan
• nilotinib
• pazopanib
• pharmacogenetics
• precision medicine

• P30 CA076292 NCI NIH HHS

• Disease
• Gender
• Interindividual variability
• Pharmacogenomics
• Pregnancy

• gastrointestinal stromal tumor
• hepatic toxicity
• real-world data
• regorafenib
• retrospective
• tyrosine kinase inhibitor

• OATP1B1
• OATP1B3
• drug-drug interactions
• tyrosine kinase inhibitors

• U24 CA247648 NCI NIH HHS
• R01CA138744 NIH HHS
• R01CA215802 NIH HHS

• cancer
• drug efficacy
• drug safety
• oncology
• personalised medicine
• pharmacogenomics

• Malignant
• Pazopanib
• Phase II
• Pleural mesothelioma

• Aged
• Aged, 80 and over
• Humans
• Indazoles
• Mesothelioma/drug therapy
• Mesothelioma, Malignant
• Middle Aged
• Pyrimidines/adverse effects
• Sulfonamides/adverse effects

• UG1 CA189971 NCI NIH HHS
• UG1 CA189825 NCI NIH HHS
• UG1 CA189956 NCI NIH HHS
• UG1 CA189872 NCI NIH HHS
• UG1 CA189861 NCI NIH HHS
• UG1 CA189847 NCI NIH HHS
• UG1 CA189858 NCI NIH HHS
• UG1 CA232760 NCI NIH HHS
• U10 CA180790 NCI NIH HHS
• U10 CA180882 NCI NIH HHS
• UG1 CA189808 NCI NIH HHS
• UG1 CA189957 NCI NIH HHS
• U10 CA180866 NCI NIH HHS
• U10 CA180821 NCI NIH HHS
• UG1 CA189816 NCI NIH HHS
• UG1 CA189805 NCI NIH HHS
• UG1 CA189812 NCI NIH HHS
• UG1 CA189863 NCI NIH HHS
• National Cancer Institute

• case report
• drug-drug-gene interactions
• hyperglycaemia
• pazopanib
• pharmacogenetics
• polypharmacy

• Drug interaction
• Organic anion-transporting polypeptide transporters
• Pharmacokinetics
• Transporters

The approved standard dose of pazopanib is 800 mg per day, but the appropriate dose of pazopanib to treat soft tissue sarcoma (STS) patients in real-world practice is controversial. Of 124 STS patients treated with pazopanib, we retrospectively analyzed the cases of STS patients who achieved progression-free survival at 12 weeks by pazopanib treatment as pazopanib responders, and we evaluated their relative dose intensity (RDI) in the initial 12 weeks (12W-RDI). We enrolled 78 STS patients in the analyses as pazopanib responders, and 54 patients of the 78 pazopanib responders (69%) were able to maintain 12W-RDI ≥80%. In landmark analyses, patients with 12W-RDI of 80% ≥80% had significantly longer progression-free survival compared to those with 12W-RDI <80% (30.7 weeks vs. 22.0 weeks, hazard ratio [HR]: 0.56 [95%CI: 0.33–0.94], p = 0.026). The most frequently observed reasons of treatment interruption and/or dose reduction of pazopanib during the initial 12 weeks were anorexia and liver function disorders. Liver toxicity was the adverse event most frequently observed in the 12W-RDI <80% patients throughout the treatment periods. Based on our results, it appears that maintaining as high a dose intensity as possible that is tolerable—at least during the initial 12 weeks—is likely to be the better option in pazopanib treatment for STS patients.

• pazopanib
• relative dose intensity
• soft tissue sarcoma
• tyrosine kinase inhibitor

Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of renal cell carcinoma and soft tissue sarcoma. Despite the high inter-patient variability in pharmacokinetic exposure, pazopanib is administered at a fixed dose of 800 mg once daily (QD). Pharmacokinetic exposure is linked to both efficacy and toxicity. In this case report, we illustrate the value of therapeutic drug monitoring by describing two patients with adequate pazopanib trough concentrations (C_min) at an eight times lower than standard dose.

Patient A is a 69-year-old woman with metastatic leiomyosarcoma who had significant toxicities and a high C_min on the standard dose. While dose reductions to 200 mg QD and later 200 mg every other day were made, pazopanib C_min remained above the efficacy threshold. Patient B is a 50-year-old male with metastatic angiosarcoma and a history of Gilbert syndrome. Pazopanib treatment was initiated at the standard dose of 800 mg QD, but was reduced to 200 mg QD 1-week-on - 1-week-off due to total bilirubin elevation. Pazopanib C_min was adequate in this patient as well.

It could be valuable to measure pazopanib levels in case of dose reductions due to toxicity, as exposure could still be adequate at considerably lower than standard doses.

• Pazopanib
• Therapeutic drug monitoring
• Toxicity

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.

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.

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.

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.

• Antineoplastic agents
• Carcinoma, renal cell
• Kidney neoplasms
• Pazopanib
• Protein kinase inhibitors
• Quality of life

• Etoposide
• Neutropenia
• Polymorphism
• Small-cell lung cancer
• UGT1A1

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Asian People/genetics
• Carboplatin/administration & dosage
• Cisplatin/administration & dosage
• Etoposide/administration & dosage
• Female
• Glucuronosyltransferase/genetics
• Granulocyte Colony-Stimulating Factor
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Male
• Neutropenia/chemically induced
• Neutropenia/genetics
• Polymorphism, Genetic
• Retrospective Studies
• Small Cell Lung Carcinoma/drug therapy
• Small Cell Lung Carcinoma/genetics
• Thrombocytopenia/chemically induced
• Thrombocytopenia/genetics

• Hyperbilirubinemia
• Polymorphisms
• Tyrosine kinase inhibitors
• UGT1A1

• Glucuronosyltransferase/antagonists & inhibitors
• Glucuronosyltransferase/genetics
• Humans
• Hyperbilirubinemia/chemically induced
• Hyperbilirubinemia/enzymology
• In Vitro Techniques
• Inhibitory Concentration 50
• Microsomes, Liver/drug effects
• Microsomes, Liver/enzymology
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/therapeutic use

• Angiogenesis
• Apatinib
• Gilbert syndrome
• Small cell lung cancer

The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations.

Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off).

Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%).

A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations.

ClinicalTrials.gov, NCT00720941, Registered July 22, 2008

ClinicalTrials.gov, NCT01147822, Registered June 22, 2010

The online version of this article (10.1186/s13045-018-0617-1) contains supplementary material, which is available to authorized users.

• Pazopanib
• Renal cell carcinoma
• Sunitinib

• Adverse drug reaction
• Molecular-targeted drug
• Pharmacodynamics
• Pharmacokinetics
• Polymorphism
• Renal cell carcinoma

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/pharmacology
• Carcinoma, Renal Cell/drug therapy
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/pathology
• Drug-Related Side Effects and Adverse Reactions/etiology
• Humans
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/genetics
• Kidney Neoplasms/pathology
• Molecular Targeted Therapy
• Polymorphism, Genetic
• Prognosis

• Administration, Intravenous
• Animals
• Cyclosporine/pharmacology
• HEK293 Cells
• Hepatocytes/metabolism
• Humans
• Indazoles
• Inhibitory Concentration 50
• Liver/cytology
• Liver/metabolism
• Male
• Metformin/pharmacokinetics
• Mice
• Mice, Inbred ICR
• Octamer Transcription Factor-1/antagonists & inhibitors
• Octamer Transcription Factor-1/metabolism
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/pharmacokinetics
• Pyrimidines/administration & dosage
• Pyrimidines/pharmacokinetics
• Quaternary Ammonium Compounds/pharmacology
• Sulfonamides/administration & dosage
• Sulfonamides/pharmacokinetics
• Tissue Distribution
• Transfection

• Angiogenesis
• Blood vessels
• Cancer
• Pazopanib
• Systemic review
• Vascular endothelial growth factor

• Uterine leiomyosarcomas
• angiogenesis
• pazopanib
• soft tissue sarcomas
• targeted drug

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.

• hepatic fibrosis
• hepatotoxicity
• tyrosine kinase inhibitors

• Animals
• Hepatic Stellate Cells/drug effects
• Humans
• Liver/drug effects
• Liver Cirrhosis/drug therapy
• Protein Kinase Inhibitors/pharmacology
• Protein-Tyrosine Kinases/antagonists & inhibitors

• Pazopanib
• clinical pharmacology
• drug-drug interactions
• metabolism
• renal cell carcinoma
• soft-tissue sarcoma
• targeted therapy
• toxicity

Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC.

• Cetuximab
• Colorectal cancer
• Metastatic
• Toxicity
• Chemotherapy

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Cetuximab/adverse effects
• Cetuximab/pharmacology
• Cetuximab/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Combined Modality Therapy
• Drug Interactions
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/immunology
• Humans
• Molecular Targeted Therapy
• Treatment Outcome

• CYP polymorphisms
• hepatitis reactivation
• hepatotoxicity
• immunotherapy
• molecular targeted therapy
• monoclonal antibodies
• multikinase inhibitors
• pharmacogenomics
• tyrosine kinase inhibitors