Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report.

Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib. Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity. Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = - 0.80, P = 0.003 and r = - 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53-0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61-1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity. Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.

Associations among regorafenib concentrations, severe adverse reactions, and ABCG2 and OATP1B1 polymorphisms.

PURPOSE: The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms. METHODS: A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters. RESULTS: Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.01 and 3.45 (2.12-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified. CONCLUSIONS: Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.

A phase II trial of prophylactic olanzapine combined with palonosetron and dexamethasone for preventing nausea and vomiting induced by cisplatin.

AIM: To investigate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for patients receiving cisplatin (≥50 mg/m(2) ), because this antiemetic therapy has not been sufficiently examined in patients receiving cisplatin. METHODS: We conducted a phase II study to evaluate the efficacy and safety of olanzapine in combination with palonosetron and dexamethasone for chemotherapy naïve patients receiving cisplatin (≥50 mg/m(2) ). Patients received prophylactic dexamethasone (20 mg IV, day 1), palonosetron (0.75 mg IV, day 1), and olanzapine (10 mg, days 1-4). The patients were monitored for emesis and nausea for 120 h after chemotherapy. The primary endpoint was the complete response (CR) rate, which was defined as no vomiting episodes and no use of rescue medication for the overall period. CR rates of 65% and 45% would indicate the potential usefulness and the lower limit of interest, respectively. RESULTS: Fifty-one patients, including 37 esophageal cancer patients were enrolled, of whom 41 (80%) completed the treatment protocol as planned. The complete response rate for the overall period was 43% (95% confidence interval: 29-58); the primary endpoint was not met. Vomiting was frequently observed, with the overall rate of 51%. Most events occurred during 24-72 h after chemotherapy. Somnolence was observed in 73% of the patients, but it was well tolerated in most cases. CONCLUSIONS: Olanzapine combined with palonosetron and dexamethasone did not prevent chemotherapy-induced nausea and vomiting induced by cisplatin as expected. The safety of this antiemetic therapy was confirmed.