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Purpose: We aimed to investigate the efficacy of 0.25 mg dose of palonosetron and granisetron in triplet antiemetic prophylaxis in breast cancer patients receiving HEC., Methods: Patients with nonmetastatic breast cancer who received HEC [doxorubicin or epirubicin plus cyclophosphamide (AC/EC)] were enrolled in the study. The prophylactic triplet antiemetic regimens were used according to the doctor's preference during the first cycle of HEC as intravenous dexamethasone and palonosetron 0.25 mg or granisetron 3 mg on day 1 as well as oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3).The primary endpoint was complete response rate (CR) on acute and delayed chemotherapy-induced nausea and vomiting (CINV), separately., Results: A total of 118 female patients were included in the study. Patients received AC (83%), EC (3%), and dose-dense AC (14%) as adjuvant (88%) or neoadjuvant (12%). The majority of patients received palonosetron (59%) containing antiemetic treatment. The CR rate on acute and delayed vomiting was very high and not statistically different in both of the arms (acute 87% vs. 96%, p = 0.089; delayed 90% vs. 92%, p = 0.489), respectively. Nevertheless, the CR rate on either acute or delayed nausea was lower than vomiting (acute 51% vs. 51%; delayed 38% vs. 29%, p = 0.203; respectively)., Conclusions: This is the second study that compared a 0.25 mg dose of palonosetron with first-generation setron in triplet antiemetic prophylaxis in cancer patients receiving HEC. We could not find meaningful statistical differences between two arms, regarding CR rate on acute and delayed CINV.

Purpose: To develop a population pharmacokinetic model of aprepitant and dexamethasone in Japanese patients with cancer, explore the factors that affect the pharmacokinetics of aprepitant, and evaluate the effect of aprepitant on the clearance of intravenous dexamethasone., Methods: A total of 897 aprepitant concentration measurements were obtained from 290 cancer patients and 25 healthy volunteers. For dexamethasone, a total of 847 measurements were obtained from 440 patients who were co-administered aprepitant (40, 125 mg, or placebo). Plasma concentration of aprepitant and dexamethasone were determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM software., Results: The plasma concentration time course of aprepitant was described using a one-compartment model with first-order absorption and lag time. Oral clearance (CL/F) of aprepitant was changed by aprepitant dose at doses of 40 or 125 mg. Body weight was the most influential intrinsic factor to CL/F of aprepitant. Age, ALT, and BUN also had mild effects on the CL/F. Typical population estimates of CL/F, apparent distribution volume (V(d)/F), absorption constant (K(a)) and absorption lag time were 1.54 L/h, 72.1 L, 0.893/h and 0.295 h, respectively. Inter-individual variability in CL/F, V(d)/F and K(a) were 53.9, 21.0, and 141%, respectively; intra-individual variability was 27.7%. The plasma concentration time course of intravenous dexamethasone was also described using a one-compartment model. Clearance of dexamethasone was decreased 24.7 and 47.5% by co-administration of aprepitant 40 and 125 mg. All final model estimates of aprepitant and dexamethasone fell within 10% of the bootstrapped mean., Conclusions: A pharmacokinetic model for aprepitant has been developed that incorporates body weight, age, ALT, BUN and aprepitant dose to predict the CL/F. The results of population pharmacokinetic analysis of dexamethasone support dose adjustment of dexamethasone in the case of co-administration with aprepitant.

Purpose: Nausea and vomiting are two of the most debilitating side effects of cytotoxic chemotherapy. Prevention of nausea and vomiting is, thus, very important to ensure that cancer patients continue to receive optimal cytotoxic therapy while seeking to maintain their quality of life. Significant advances in antiemetic therapy have been achieved since the introduction of the 5-HT(3) receptor antagonists, and these agents are currently regarded as first-line antiemetic agents. The aim of this article is to examine the hypothesis that there is a dose-response effect of granisetron for preventing chemotherapy-induced nausea and vomiting in cancer patients., Methods: A literature review of relevant publications was undertaken to provide a comprehensive review of issues related to the control of chemotherapy-induced emesis with escalating doses of granisetron., Results: There is evidence to suggest that there is a significant trend towards an improved efficacy of granisetron-in both the control of emesis and secondary end-points such as nausea and anorexia-with increasing doses, up to 40 micro g/kg, in adults. At this dose, the likelihood of treatment success may be enhanced for most patients regardless of their individual emetogenic risk. Additionally, incremental doses of granisetron (up to 9 mg) have been shown to be effective and well tolerated in patients with refractory emesis., Conclusions: Those patients experiencing inadequate control of nausea and vomiting following granisetron may also benefit from retreatment with supplementary doses of granisetron, and over subsequent chemotherapy cycles, these patients should receive granisetron 40 micro g/kg to ensure emesis protection.

Purpose: The antiemetic effect of granisetron injection at a dose of 40 microg/kg used in the treatment of nausea/vomiting induced by multidrug combined cancer chemotherapy excluding cisplatin in patients with tumors of hematopoietic organs was evaluated by comparing a 30-min infusion and a slow intravenous injection given over 30 s., Methods: A two-group random-allocation comparative study was performed with the cooperation of multiple institutions using a central registration system., Results: In the treatment of acute clinical symptoms, appetite was described as "similar to that during good health" by 61.1% of patients (55/93) in the instillation group and by 47.3% (44/93) in the slow injection group, a significant advantage in the infusion group. However, no significant differences in the number of episodes of vomiting, the severity of nausea or clinical efficacy were found. In the final clinical evaluation and assessment of usefulness based on the subjective judgement of physicians throughout the entire therapeutic period, no differences were discernible. No side effects were reported for either method and there was no indication of a sex difference concerning efficacy. However, the efficacy in patients with an anemic tendency was slightly inferior., Conclusions: The maintenance of appetite during the administration of anticancer drugs is very important to maintain patients' daily activities and quality of life. The present results support the usefulness of infusion of granisetron as an administration method during chemotherapy for malignant hemopathy.

Commercially available serotonin-type 3 (5-HT3) receptor antagonists (ondansetron, granisetron, and tropisetron) have shown no clinically significant adverse effects on the cardiovascular system. In the dose-ranging evaluation of dolasetron, computer-generated ECGs revealed clinically asymptomatic prolongations of ECG intervals. We performed a clinical trial in which the possible changes in ECG intervals following a single 3-mg i.v. injection of granisetron and an injection of either doxorubicin or epirubicin were registered using computerized ECG analysis in cancer patients. A total of 30 patients who were designated to receive 3 mg granisetron i.v. for the prophylaxis of emesis induced by doxorubicin or epirubicin were entered into the study. Computer-generated ECG tracings were obtained before treatment, following the injection of 3mg granisetron, and immediately after doxorubicin or epirubicin injection. The mean PR interval duration increased from 160 to 166 ms after granisetron infusion (P=0.02). Doxorubicin and epirubicin did not potentiate this change. There was no statistically significant change in cardiac rhythm, QRS duration, or QTc intervals. The observed minor changes in the PR time following i.v. injection of granisetron do not seem to be of clinical relevance.

Granisetron is a highly potent and selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 micrograms/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequently reported adverse events were constipation (n = 6) and headache (n = 5). Maximal plasma levels of granisetron were within the range of 44.57-410 ng/ml except in one patient. The median values recorded for peak concentration (Cmax) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml-1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.