Support Care Cancer (2014) 22:1959–1964 DOI 10.1007/s00520-014-2179-2

ORIGINAL ARTICLE

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy Yosuke Ikari & Kentaro Ogata & Yuta Nakashima & Eiichi Sato & Michio Masaki & Hiroo Katsuya & Toshitaka Goto & Toshihiro Tanaka & Kenji Ishitsuka & Yasushi Takamatsu & Shuuji Hara & Kazuo Tamura

Received: 11 September 2013 / Accepted: 10 February 2014 / Published online: 4 March 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The aims of this study were to evaluate the safety, efficacy, and pharmacokinetics of repeated doses of palonosetron 0.75 mg on days 1 and 3 in Japanese patients who received highly or moderately emetogenic chemotherapy. Methods Twenty- six patients received palonosetron 0.75 mg intravenously before chemotherapy on days 1 and 3 plus dexamethasone (12–16 mg before chemotherapy on day 1 and 4–8 mg on days 2 and 3). The primary endpoints were safety and pharmacokinetics. Pharmacokinetics were evaluated in a subset of patients (n=6). Complete response and complete protection were evaluated as secondary endpoints. Results The accumulation ratios for Cmax and AUClast after the second dose on day 3 were 1.42 and 1.37, respectively. These values were consistent with the theoretical values expected from the half-life of palonosetron on day 1. Almost all of the patients had no nausea or vomiting in the acute phase (complete response (CR) rate, 96.2 % [25/26]; CP rate, 92.3 % [24/26]). In the delayed phase (24–192 h post-chemotherapy), the complete response and complete protection rates were 76.9 % (20/26) and 61.5 % (16/26), respectively. Treatment was well tolerated. Conclusions This is the first study to report the pharmacokinetics of multiple doses of palonosetron 0.75 mg, given on Y. Ikari (*) : Y. Nakashima : E. Sato : M. Masaki : H. Katsuya : T. Goto : T. Tanaka : K. Ishitsuka : Y. Takamatsu : K. Tamura Division of Medical Oncology, Hematology and Infectious Diseases, Department of Internal Medicine, School of Medicine, Fukuoka University, Nanakuma, Jyonan-ku, Fukuoka, Japan e-mail: [email protected] K. Ogata : S. Hara Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan

days 1 and 3, in Japanese patients. Repeated treatment with palonosetron was safe and well tolerated by patients who received highly or moderately emetogenic anticancer chemotherapy.

Keywords Palonosetron . Multiple-day chemotherapy . Antiemetics . Chemotherapy-induced nausea and vomiting . Pharmacokinetics

Introduction Chemotherapy-induced nausea and vomiting (CINV) is one of the most problematic adverse events in patients who receive chemotherapy. CINV could lead to interruption of chemotherapy, poor compliance with treatment, and a reduced quality of life. CINV is triggered by afferent impulses to the vomiting center from the chemoreceptor trigger zone, pharynx and gastrointestinal tract, and cerebral cortex. The principal neuroreceptors involved in the emetic response are 5-HT3 and dopamine receptors. Palonosetron is an antiemetic agent with a long half-life (approximately 40 h), which markedly differs from conventional 5-HT3 antagonists. Palonosetron has a peculiar mechanism of action that may be the reason of its prolonged duration of 5-HT3 receptor inhibition, differently from the other firstgeneration 5-HT3 receptor antagonists [1]. Double-blind controlled clinical trials have established that palonosetron is safe and effective in patients receiving single-day highly emetogenic chemotherapy [2]. In patients who receive multiple-day chemotherapy, however, the optimal treatment regimen, either daily or less frequently, remains unclear [3].

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Janes et al. studied the urinary excretion of 5hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, during multiple-day, high-dose chemotherapy. The peak 5-HIAA level in urine was observed within the first 24 h after treatment, with no further peaks thereafter. This finding suggested that some mechanism responsible for emesis occurring 2 to 3 days postchemotherapy and subsequently during multiple-day chemotherapy is at least partially serotonin independent [4]. However, the same group also reported a significantly increased level of 5-HIAA in urine up to 5 days after the start of chemotherapy as compared with the baseline value, suggesting that 5-HT3-dependent emetic signals are also sustained for 5 days. Although standard treatment is established as NK-1 receptor antagonist+5-HT3 antagonists+dexamethasone in HEC and 5-HT3 antagonist+dexamethasone in MEC [5], prevention of nausea and vomiting in multiple-day chemotherapy remains to be problematic. One of the important factors to further improve the antiemetic treatment in this setting is the longer duration of 5-HT3 receptor inhibition. To date, a limited number of studies have evaluated repeated doses of palonosetron 0.25 mg in patients who received multiple-day chemotherapy [6–8]. In Japan, the approved dose of palonosetron is 0.75 mg, which is threefold higher than the recommended dose in the USA and Europe. Recommended dose of palonosetron in Japan was selected based on two dose-finding studies (PALO-H [9], PALO-M [10]) conducted in Japanese patients. When comparing three doses of palonosetron (0.075, 0.25, and 0.75 mg), complete response (CR) rate in delayed nausea and vomiting was highest in the 0.75 mg arm, and since no difference in safety were observed among the dose arms, 0.75 mg was chosen as the recommended dose to be studied in the phase III study. In the phase III study (PROTECT), palonosetron 0.75 mg showed noninferiority in the acute phase and superiority in the delayed phase against granisetron, and the safety profile was similar between the two arms [2]. At present, repeated treatment with palonosetron 0.75 mg within a 7-day interval is not recommended in Japan because the safety and efficacy of frequent (consecutive or alternate day) treatment has not been evaluated. To optimize the antiemetic regimen of palonosetron for patients who receive multiple-day chemotherapy in Japan, studies of the safety and pharmacokinetics of repeated doses of palonosetron 0.75 mg in Japanese subjects are essential. The present study was designed to evaluate the safety and efficacy of repeated treatment with palonosetron 0.75 mg on days 1 and 3 in patients who received single- and multiple-day highly or moderately emetogenic chemotherapy. The pharmacokinetics of palonosetron were also investigated in a subgroup of patients with hematologic malignancy, and the concentration-time profile after repeat doses of palonosetron 0.75 mg on days 1 and 3 was evaluated.

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Patients and methods Patients The study group comprised 26 adults 20 years or older who received highly or moderately emetogenic chemotherapy. All subjects had a performance status of 0 to 2 and adequate hepatic, renal, and bone marrow functions and provided written informed consent for participation in the study. Patients were excluded if they had a corrected QT interval (QTc) of >450 ms on 12-lead electrocardiography or had a history of hypersensitivity to palonosetron, other 5-HT3 receptor antagonists, or the components of dexamethasone sodium phosphate. Methods Thirty minutes after an intravenous bolus dose of palonosetron (0.75 mg/patient), highly or moderately emetogenic anticancer chemotherapy was administered. The day on which patients received highly or moderately emetogenic chemotherapy was designated as day 1. Subsequently, another intravenous bolus dose of palonosetron (0.75 mg/patient) was given on day 3. Dexamethasone sodium phosphate was given in a dose of 12–16 mg/patient before treatment with palonosetron, followed by 4–8 mg/patient from day 2 onward. However, if steroids were included in the treatment regimen (as an antitumor agent), this schedule did not apply. During the safety observation period from 24 h before administration of palonosetron until 8 days after administration, the use of antiemetic agents was defined as antiemetic treatment. Whether to use aprepitant prophylactically was left to the discretion of the physician in charge. The study variables were evaluated for 8 days after the initial dose of chemotherapy (from 0 to 192 h). The primary endpoints were safety and pharmacokinetics, and the secondary endpoint was efficacy. The analysis for efficacy was performed on the full analysis set (FAS) data. The FAS cohort included all registered patients after minimal and justified elimination. The safety cohort included all patients who received study drug. Six of the 26 patients were enrolled in the pharmacokinetic part of this study. At least 3 mL of blood samples were drawn into heparinized vacutainers 15 min; 30 min; and 1, 4, 8, and 24 h after the first dose of palonosetron on day 1. On day 3, blood samples were collected before the second dose of palonosetron and 15 min; 30 min; and 1, 4, 8, 24, and 48 h after the second dose. Palonosetron was administered intravenously on days 1 and 3, 30 min before the start of highly or moderately emetogenic chemotherapy. The times of blood sampling were defined as the times from the start of palonosetron treatment. Plasma samples were prepared and

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Table 1 Characteristics of study patients FAS

PK patients

Number of patients Median age (range) Gender, n (%) Male Female Tumor type, n (%) Hematologic malignancies Malignant lymphoma Acute myeloid leukemia Multiple myeloma Acute lymphoblastic leukemia Histiocytic sarcoma Solid tumor Breast cancer Rectal cancer Fallopian tube cancer Thymic carcinoma

26 59 (31–72)

6 57.5 (50–67)

10 (38.5) 16 (61.5)

3 (50.0) 3 (50.0)

19 (73.1) 10 (38.5) 6 (23.1) 1 (3.8) 1 (3.8) 1 (3.8) 7 (26.9) 3 (11.5) 1 (3.8) 1 (3.8) 1 (3.8)

6 (100.0) 2 (33.3) 3 (50.0) 1 (16.7)

Rhabdomyosarcoma Chemotherapy regimen, n (%) High emetic risk Hyper-CVAD CHOP HD-MTX plus Ara-C LEED FEC ICE AC CAP EPOCH Moderate emetic risk HD-Ara-C HD melphalan Bendamustine Calboplatin plus paclitaxel CDE-11 FOLFIRI plus bevacizumab

1 (3.8)

VAC Ara-C plus etopocide Duration of chemotherapy 1 Day 2 Days 3 Days 4 Days 5 Days 6 Days Concomitant use of aprepitant No Yes

12 (46.2) 1 (3.8) 2 (7.7) 2 (7.7) 2 (7.7) 1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8) 14 (53.8) 5 (19.2) 1 (3.8) 1 (3.8) 2 (7.7) 2 (7.7) 1 (3.8)

1 (16.7) 1 (16.7)

5 (83.3) 3 (50.0) 1 (16.7) 1 (16.7)

1 (3.8) 1 (3.8) 7 (26.9) 3 (11.5) 5 (19.2) 3 (11.5) 7 (26.9) 1 (3.8) 19 (73.1) 7 (26.9)

FAS full analysis set; Hyper-CVAD fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; CHOP cyclophosphamide, vincristine, doxorubicin, and prednisolone; HD-MTX plus Ara-C highdose methotrexate plus cytarabine; LEED melphalan, cyclophosphamide, mesna, and etoposide; FEC fluorouracil, epirubicin, and cyclophosphamide; ICE ifosfamide, carboplatin, and etoposide; AC doxorubicin and cyclophosphamide; CAP cyclophosphamide, doxorubicin, and cisplatin; EPOCH etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisolone; HD-AraC high-dose cytarabine; HD melphalan high-dose melphalan; CDE-11:CPT-11 dexamethasone and etoposide; FOLFIRI fluorouracil, irinotecan, and folinic acid; VAC vincristine, actinomycin D, and cyclophosphamide

analyzed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of palonosetron, which was expressed as the concentration of palonosetron free base. Pharmacokinetic variables of palonosetron were calculated for individual patients and are summarized according to each day of treatment (days 1 and 3). The following pharmacokinetic variables were calculated for individual patients by noncompartmental analysis using WinNonlin®, version 6.1 (Pharsight Corporation, Sunnyvale, CA, USA): T1/2, Tmax, Cmax, AUC0–24h, AUClast, AUCinf, volume of distribution calculated from the elimination phase (Vdz), and total body clearance (CLtot). AUC0–24h reflects the total exposure to palonosetron in the acute phase up to 24 h after treatment, and AUClast reflects the total exposure to palonosetron up to 48 h after treatment. Accumulation ratios (days 3/1) were calculated for both Cmax (R1) and AUClast (R2). Safety was evaluated on the basis of the results of blood tests, blood chemical analysis, and electrocardiography. Signs and symptoms were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and those that increased in grade as compared with before treatment were regarded to be adverse events. To evaluate efficacy, CINV developing within 24 h after administration of anticancer chemotherapy was defined as acute nausea and vomiting, and CINV that occurred after 24 to 192 h was defined as delayed nausea and vomiting. No emetic episodes and no use of rescue medication were defined as CR. No emetic episodes, no use of rescue medication, and no significant nausea were defined as complete protection (CP). Efficacy was evaluated on the basis of a patient diary. This study was approved by the ethics committee of Fukuoka University Hospital.

2 (33.3) 1 (16.7) 3 (50.0)

6 (100.0) 0 (0.0)

Results A total of 26 patients were enrolled from July 2011 through June 2012. Table 1 shows the demographic characteristics of the patients. All 26 patients were included in the full analysis set and the analysis of safety, and six were included in the analysis of pharmacokinetics. There was a preponderance of

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were consistent with the theoretical values expected on the basis of the half-life of palonosetron on day 1. Safety and efficacy results

Fig. 1 Mean plasma concentration-time profile of palonosetron after repeated intravenous administration of 0.75 mg palonosetron on days 1 and 3 (mean±SD, n=6)

women (61.5 %) and hematologic malignancy (73.1 %). Of the patients, 74.1 % had received chemotherapy for 2–6 days (median, 3 days). Pharmacokinetics A total of six patients (three men and three women) who were 50 to 67 years of age participated in the pharmacokinetic part of this study. Their primary diseases were leukemia, lymphoma, and myeloma. All patients were heavily treated with intensive chemotherapy which included high-dose cytarabine, R-hyperCVAD, bendamustine, or high-dose melphalan. The mean plasma concentration-time profile of palonosetron is shown in Fig. 1, and the calculated pharmacokinetic variables are summarized in Table 2. Maximum plasma drug concentrations were obtained at the time of taking the first blood sample in 15 min after administration in all patients. The plasma drug concentration then declined in a multiexponential manner, with a terminal half-life of approximately 40 h. The accumulation ratios of Cmax and AUClast after the second dose on day 3 were 1.42 and 1.37, respectively, which

Adverse events occurring in the 26 patients are summarized in Table 3. The main treatment-related adverse events were constipation (77.0 %), diarrhea (15.4 %), pain (7.7 %), and fever (7.7 %). No patient had grade 3 or higher serious adverse events. Efficacy endpoints are shown in Fig. 2. Almost all of the patients had no nausea or vomiting in the acute phase (CR rate, 96.2 % [25/26]; CP rate, 92.3 % [24/26]). In the delayed phase, the CR rate was 76.9 % (20/26), and the CP rate was 61.5 % (16/26). The rate of no nausea in the acute phase was 80.8 % (21/26) and in the delayed phase was 53.8 % (14/26).

Discussion This is the first study to evaluate the pharmacokinetics of palonosetron 0.75 mg given repeatedly in Japanese patients. Concentration-time profiles of palonosetron were evaluated in six patients who received repeated treatment with palonosetron on days 1 and 3. Maemondo et al. reported the pharmacokinetics of palonosetron in Japanese patients who received highly emetogenic chemotherapy [9]. The mean pharmacokinetic variables on day 1 in our study were strongly consistent with those reported by Maemondo et al. for patients who received palonosetron 0.75 mg, suggesting that similar exposure to palonosetron can be expected in patients with hematologic malignancy. After the second dose of palonosetron on day 3, Cmax increased by 1.42-fold and AUClast increased by 1.37-fold as compared with the respective values on day 1. Although palonosetron exhibited multi-exponential elimination, the carryover ratio from days 1 on 3 could be roughly calculated from its half-life, i.e., exp (−Kel ·τ), where Kel is the elimination rate constant, which is equal to ln (2)/T1/2 (0.0176 on day 1), and τ is the time interval between the multiple doses, which was 48 h in

Table 2 Pharmacokinetic variables of palonosetron after repeated intravenous administration of 0.75 mg palonosetron on days 1 and 3

Day 1

Day 3

T1/2 (h)

Tmax (h)

Cmax (ng/mL)

AUC0–24h (ng·h/mL)

AUClast (ng·h/mL)

AUCinf (ng·h/mL)

Vdz (L)

CLtot (L/h)

CLtot (mL/min)

Mean SD %CV Mean

39.4 8.5 21.5% 42.5

0.26 0.02 6.4% 0.40

2.05 0.63 30.9% 2.90

26.0 5.3 20.3% 35.2

42.4 9.0 21.1% 58.3

76.0 20.5 27.0% 108.9

580 132 22.7%

10.6 3.2 29.9%

176 53 29.9%

SD %CV

5.9 13.8%

0.31 77.8%

0.99 34.2%

8.4 23.8%

13.5 23.2%

22.2 20.4%

a

R1, accumulation ratio of Cmax

b

R2, accumulation ratio of AUClast

R1a (Cmax)

R2b (AUClast)

1.42

1.37

0.18 12.7%

0.13 9.4%

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Table 3 Treatment-related adverse events (n=26) Patients, n (%) Adverse event

Grade 1

Grade 2

Grade 3

Constipation Diarrhea Pain Fever Increased ALT Increased AST Prolonged QTc Total bilirubin increased Increased γ-GTP

10 (38.5) 4 (15.4) 1 (3.8) 2 (7.7) 7 (27.0) 6 (23.1) 4 (15.4) 3 (11.5) 2 (7.7)

10 (38.5) 0 (0.0) 1 (3.8) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

AST aspartate aminotransferase, ALT alanine aminotransferase, QTc corrected QT interval, γ-GTP gamma-glutamyltransferase

the treatment regimen we studied. The theoretically calculated value for the carryover ratio is 0.43, which is well consistent with observed values for the accumulation ratios of Cmax and AUClast, suggesting that an unexpectedly higher increase in exposure to palonosetron is unlikely after repeat doses. Einhorn et al. reported the pharmacokinetics of palonosetron after repeat doses of 0.25 mg on days 1, 3, and 5. Although they measured the concentration of palonosetron in plasma only up to 2.5 h after each dose, 1.42-fold accumulation was apparent on the basis of the days 5 to 1 AUC0–t ratio [6]. Hunt et al. investigated the detailed pharmacokinetics of palonosetron 0.25 mg given for three consecutive days to healthy subjects. The 2.1-fold accumulation of palonosetron in plasma after three daily doses of 0.25 mg was expected, given that the elimination half-life of palonosetron is approximately 40 h [5]. These previously reported results were also consistent with our findings, suggesting that similar accumulation of palonosetron occurs regardless of the dose level. After the second dose of palonosetron, the mean Cmax increased to 2.9 ng/mL, and the mean AUCinf increased to

108.9 ng·h/mL. Consequently, the mean overall AUC was estimated to be 151.3 ng·h/mL (the sum of AUClast on day 1 and AUCinf on day 3). These values were higher than those obtained after typical therapeutic exposure to palonosetron in the study by Maemondo et al. In our study, repeated treatment with palonosetron on days 1 and 3 was safe and well tolerated in 26 patients who received highly or moderately emetogenic chemotherapy. Tolerability to palonosetron has been evaluated in healthy subjects by Stoltz et al. [11]. In their study, 60 American and 24 Japanese healthy subjects received a single dose of palonosetron in levels ranging from 0.3 to 90 μg/kg. At the highest dose level in Japanese subjects (typically 5.4 mg/subject for subjects with a body weight of 60 kg), mean Cmax and AUCinf were 52.6 ng/mL and 561 ng·h/mL, respectively. They also reported that the incidences and severities of adverse events were similar in subjects who received palonosetron and those who received placebo, with no dosedependent increases. The most frequent adverse events were mild to moderate headache, transient elevation of liver enzymes, and constipation. The safety profile of palonosetron in their study was consistent with our findings. As for safety in our study, constipation occurred in 20 patients (77.0 %), but could be managed by oral treatment with laxatives. The incidences of other adverse events were similar to those after single-dose treatment with palonosetron. QT prolongation was more frequently observed (15.4 %) than at the time of palonosetron single-dose administration (2.7 %); however, it was all grade 1 and did not raise any clinical concerns [2]. As for efficacy, although 19 of the 26 patients received multiple-day regimens of chemotherapy, the CR rate was 96.2 % in the acute phase and 76.9 % in the delayed phase, indicating that the control of CINV was generally good. However, although delayed nausea did not develop in 46.2 % of the patients, it was inadequately controlled in about half of the patients, indicating the need for improved management of delayed nausea in the future. Our results confirmed that repeated treatment with palonosetron 0.75 mg is safe and tolerable.

Conclusion This is the first study to report the pharmacokinetics of palonosetron 0.75 mg given repeatedly (days 1 and 3) in Japanese patients. Repeated treatment with palonosetron was safe and well tolerated in patients who received highly or moderately emetogenic anticancer chemotherapy.

Fig. 2 Efficacy endpoints—complete response (defined as no emetic episodes and no use of rescue medication) and complete protection (defined as no emetic episodes, no use of rescue medication, and no clinically significant nausea)

Acknowledgments This clinical study was supported by the nonprofit organization of the Clinical Hematology/Oncology Treatment Study Group (CHOT-SG). There was no financial disclosure from any authors. We thank all patients and their families; project managers, Ms. Y. Ito and N. Gushima, and secretaries, Ms. E. Kumakawa and N. Ikoma for their valuable assistance in conducting the present study; and the medical staff of Fukuoka University for participating in this study; H. Sasaki.

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References 7. 1. Rojas C, Slusher BS (2012) Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapyinduced nausea and vomiting. Eur J Pharmacol 684 2. Saito M, Aogi K, Sekine I, Yoshizawa H, Yanagita Y, Sakai H, Inoue K, Kitagawa C, Ogura T, Mitsuhashi S (2009) Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 10(2):115–124 3. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, Chesney M, Clark-Snow RA, Flaherty AM, Freundlich B, Morrow G, Rao KV, Schwartz RN, Lyman GH (2011) Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29(31):4189–4198 4. Janes RJ, Muhonen T, Karjalainen UP, Wiklund T (1998) Urinary 5hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy. Eur J Cancer 34(1):196–198 5. Einhorn LH, Grunberg SM, Rapoport B, Rittenberg C, Feyer P (2011) Antiemetic therapy for multiple-day chemotherapy and additional topics consisting of rescue antiemetics and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer 19(Suppl 1):S1–S4 6. Einhorn LH, Brames MJ, Dreicer R, Nichols CR, Cullen MT Jr, Bubalo J (2007) Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving

8.

9.

10.

11.

multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer 15:1293–1300 Giralt SA, Mangan KF, Maziarz RT, Bubalo JS, Beveridge R, Hurd DD, Mendoza FL, Rubenstein EB, DeGroot TJ, Schuster MW (2010) Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation. Ann Oncol 22(4):939–946 Musso M, Scalone R, Bonanno V, Crescimanno A, Polizzi V, Porretto F, Bianchini C, Perrone T (2009) Palonosetron (Aloxi) and dexamethasone for the prevention of acute and delayed nausea and vomiting in patients receiving multiple-day chemotherapy. Support Care Cancer 17(2):205–209 Maemondo M, Masuda N, Sekine I, Kubota K, Segawa Y, Shibuya M, Imamura F, Katakami N, Hida T, Takeo S, PALO Japanese Cooperative Study Group (2009) A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy. Ann Oncol 20(11): 1860–1866 Segawa Y, Aogi K, Inoue K, Sano M, Sekine I, Tokuda Y, Isobe H, Ogura T, Tsuboi M, Atagi S, PALO Japanese Cooperative Study Group (2009) A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy. Ann Oncol 20(11):1874–1880 Stoltz R, Cyong JC, Shah A, Parisi S (2004) Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol 44(5):520–531

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy.

The aims of this study were to evaluate the safety, efficacy, and pharmacokinetics of repeated doses of palonosetron 0.75 mg on days 1 and 3 in Japane...
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