Sunitinib is a broad-spectrum multitargeted tyrosine kinase inhibitor mainly used as second-line therapy for non-resectable gastrointestinal stromal or first-line treatment option of metastatic renal cell carcinoma (mRCC), and as an "off-label" option in pediatric oncology. It has been previously reported that sunitinib elevates the mean corpuscular volume of erythrocytes (MCV) in treated subjects. The aim of this study was to assess time-dependent changes of this effect and evaluate its possible clinical relevance. In this study, 179 adult and 21 pediatric patients with solid tumors treated with sunitinib were retrospectively analyzed. The laboratory and treatment-related data were collected for each treatment period. The regression model with a broken-line relationship was used to fit time dependence of the MCV. In the adult group, the MCV was increasing during the first 21.6 weeks (median) of treatment in a median level of 99.8 fL, where it stabilized. MCV increase was faster in the patients who suffered from treatment-related adverse events (21.3 vs. 24.6 weeks, p = 0.010). In the pediatric cohort, the MCV dynamics were similar to adults. In conclusion, MCV changes during sunitinib treatment in pediatric and adult patients may be of clinical utility in monitoring sunitinib treatment course.

• Klíčová slova
• MCV, mean corpuscular volume, sunitinib, toxicity,
• MeSH
• dítě MeSH
• dospělí MeSH
• erytrocytární znaky MeSH
• indoly škodlivé účinky   MeSH
• karcinom z renálních buněk * farmakoterapie   patologie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   patologie   MeSH
• protinádorové látky * škodlivé účinky   MeSH
• pyrroly škodlivé účinky   MeSH
• retrospektivní studie MeSH
• sunitinib farmakologie   terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• indoly MeSH
• protinádorové látky * MeSH
• pyrroly MeSH
• sunitinib MeSH

BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSIONS: 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.

• Klíčová slova
• Clarithromycin, Drug induced liver injury (DILI), Fatal liver failure, Hepatotoxicity, Renal cell carcinoma, Roussel Uclaf causality assessment method (RUCAM), TKI,
• MeSH
• chronické poškození jater způsobené chemickými látkami * MeSH
• karcinom z renálních buněk * farmakoterapie   MeSH
• lékové postižení jater * etiologie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   MeSH
• tyrosin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH
• Názvy látek
• tyrosin MeSH

BACKGROUND: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

• Klíčová slova
• Gastrointestinal stromal tumor, Pediatric, Pharmacokinetics, Safety, Sunitinib,
• MeSH
• chemorezistence MeSH
• doba přežití bez progrese choroby MeSH
• gastrointestinální nádory farmakoterapie   patologie   MeSH
• gastrointestinální stromální tumory farmakoterapie   patologie   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• lidé MeSH
• mladiství MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• sunitinib aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imatinib mesylát MeSH
• protinádorové látky MeSH
• sunitinib MeSH