1 California Cancer Care, Greenbrae, CA; 2 VA Medical Center, Reno, NV; 3 Medical College of Wisconsin, Milwaukee, WI; 4 University of California at San Francisco, San Francisco, CA, USA; 5 Helsinn Healthcare SA, Lugano, Switzerland
Received 12 March 2003; revised 28 July 2003; accepted 4 September 2003
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ABSTRACT |
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Although currently available 5-hydroxytryptamine type 3 receptor (5-HT3) antagonists are effective, not all patients receiving these agents achieve adequate control of chemotherapy-induced nausea and vomiting (CINV). Palonosetron, a potent and highly selective 5-HT3 antagonist with a strong affinity for 5-HT3 and a prolonged plasma elimination half-life, may provide a longer duration of action than other approved agents.
Patients and methods:
One hundred and sixty-one patients were randomly assigned to receive a single intravenous bolus dose of palonosetron (0.3, 1, 3, 10, 30 or 90 µg/kg) before administration of highly emetogenic chemotherapy, with no pretreatment with corticosteroids.
Results:
The four highest doses of palonosetron were similarly effective during the first 24 h, producing clearly higher complete response (CR) (no emesis, no rescue medication) rates in the 3, 10, 30 and 90 µg/kg groups (46%, 40%, 50% and 46%, respectively) than in the 0.31 µg/kg group (24%) of evaluable patients (n = 148). The 3 µg/kg dose was identified as the lowest effective dose. A single dose of palonosetron showed prolonged efficacy in preventing delayed emesis, with approximately one-third of patients who received palonosetron 10 or 30 µg/kg maintaining a CR throughout the 7-day period following chemotherapy administration. Dose-proportional increases in pharmacokinetic parameters and a long plasma half-life (43.7128 h) were observed. Palonosetron was well-tolerated, with no doseresponse effect evident for the incidence or intensity of adverse events.
Conclusions:
Palonosetron is an effective and well-tolerated agent for the prevention of CINV following highly emetogenic chemotherapy, with 3 and 10 µg/kg identified as the lowest effective palonosetron doses.
Key words: chemotherapy, dose-ranging, emesis, 5-hydroxytryptamine type 3 receptor antagonist, nausea, palonosetron
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Introduction |
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Palonosetron is a potent and selective 5-HT3 antagonist with a high affinity for 5-HT3 receptors (pKi = 10.45 in cultured mouse neuroblastomarat glioma hybridoma cells) [8] compared with granisetron (pKi = 8.91 in cultured mouse neuroblastomarat glioma hybridoma cells) [8], ondansetron (pKi = 8.39 in cultured mouse neuroblastomarat glioma hybridoma cells) [8], dolasetron (pKi = 7.6 in cultured neuroblastoma glioma cells) [9], tropisetron (pKi = 8.81 in cultured mouse neuroblastomarat glioma hybridoma cells) [8, 10], and azasetron (Ki = 0.33 nM in the small intestines of rats) [11]. In contrast to other 5-HT3 antagonists that exist as racemic mixtures, palonosetron exists as a single stereoisomer, with improved pharmacological and pharmacokinetic profiles [12]. In preclinical studies, palonosetron demonstrated potent antiemetic properties in several standard animal models [13]. In previous phase I studies in healthy volunteers, intravenous (i.v.) palonosetron (0.390 µg/kg) was found to be well-tolerated, with mean plasma elimination half-life (T1/2) values of 40 h [13], substantially longer than that of ondansetron (46 h) [14], hydrodolasetron (the active metabolite of dolasetron; 7 h) [15], granisetron (58 h), tropisetron (7 h) and azasetron (9 h) [2, 16, 17]. Its high antiemetic potency, high binding affinity, and longer T1/2 give palonosetron the potential to provide more complete and prolonged protection against CINV compared with currently available 5-HT3 antagonists. The primary objective of this study was to determine the doseresponse relationship of single i.v. doses of palonosetron (0.390 µg/kg) in chemotherapy-naive patients receiving highly emetogenic chemotherapy, in order to identify the lowest effective palonosetron dose that produces maximal efficacy. Additional objectives included the assessment of safety and the pharmacokinetics of palonosetron over the range of doses evaluated.
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Subjects and methods |
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Exclusion criteria included severe, uncontrolled, concurrent illness other than neoplasia; unstable metastases to the brain; a history of seizures during adulthood; gastric outlet or intestinal obstruction; known vomiting within 24 h preceding palonosetron dosing; a known hypersensitivity to other 5-HT3 antagonists; previous or current exposure to highly emetogenic chemotherapies (i.e. dacarbazine, nitrosoureas or mechlorethamine); and participation in another drug study or receipt of any investigational agents within 30 days of study entry. Patients were excluded if they had received, within 24 h before receipt of study medication, any antiemetic, sedative, corticosteroid, or other drug, that, in the opinion of the investigator, could influence the results of the study. All patients (men and women) were required to practice adequate contraception for 1 month after palonosetron dosing.
Study design
This was a randomized, double-blind, multicenter, parallel-design study conducted within the United States. Thirty minutes before the start of scheduled administration of highly emetogenic chemotherapy, patients received a single i.v. bolus of palonosetron 0.3, 1, 3, 10, 30 or 90 µg/kg over 30 s. Initial palonosetron dosing ranged from 0.330 µg/kg. However, because the lowest dose (0.3 µg/kg) was thought to possibly be too low to provide adequate protection against CINV, a protocol amendment eliminated the use of this dose and a 90 µg/kg dose group was added, without breaking the study-blind. Efficacy data from the two patients who received the 0.3 µg/kg dose were pooled with the 1 µg/kg group data. No concomitant corticosteroids were administered prophylactically. For ethical reasons, placebo was not a feasible option for a control group.
All patients were observed in the hospital or clinic for a minimum of 6 h after dosing and subsequently followed for 14 days after administration of palonosetron. Blood samples from patients at selected study sites were collected at specific intervals for pharmacokinetic analysis. The study protocol was approved by the Institutional Review Board of each participating study site. All patients provided written informed consent before being enrolled in the study.
Study visits and assessment procedures
During the week before palonosetron dosing, patients underwent a complete physical examination, laboratory assessment (i.e. hematology, blood chemistry, urinalysis), vital sign measurement, and 12-lead electrocardiogram (ECG). One hour before the start of chemotherapy, sitting blood pressure and heart rate were measured, and patients completed a pre-dose nausea assessment that consisted of a categorical scale of nausea (none, mild, moderate, or severe). Blood pressure and heart rate were measured 20 min before chemotherapy initiation, throughout the 6-h observation period following treatment, and at 24 h after the start of chemotherapy. Patients used diary cards to report the number of emetic episodes and degree of nausea at 2, 4, 8, 12 and 24 h after the start of chemotherapy, as well as time of their first emetic episode (if any). Patient satisfaction with control of nausea and vomiting was evaluated every 24 h via a 100-mm visual analog scale ranging from 0 (not at all satisfied) to 100 (completely satisfied). Patients were instructed to continue to record emetic episodes for 1 week after dosing and to rate, on a daily basis, the degree of nausea or the sensation of having to vomit and the degree of satisfaction with the control of nausea and vomiting.
Twenty-four hours following chemotherapy initiation, patients returned to the clinic (if not hospitalized) to report adverse events (AEs) and concomitant medications and to undergo a limited physical examination, a 12-lead ECG, blood tests and urinalysis. Patients again returned to the clinic 1 week after dosing for a limited physical examination, clinical laboratory evaluation, and a 12-lead ECG if the 24-h ECG was significantly different from the screening ECG. AEs and concomitant medications were recorded and diary cards were collected. All patients were contacted 14 days after dosing and questioned regarding nausea and vomiting, concomitant medications and AEs. Any AEs that persisted beyond the 14-day follow-up period were followed until resolution or explanation, or until 1 month after the dose.
Therapeutic response was evaluated by recording the occurrence of an emetic episode, the degree of nausea, and the need for rescue medication. An emetic episode was defined as (i) a single vomit of solid or liquid gastric contents; (ii) a single retch, or dry heave, that did not produce solid or liquid gastric contents; or (iii) any episode of continuous vomiting or retching. Episodes separated from each other by the absence of retching or vomiting for at least 1 min were considered separate emetic episodes. Rescue medication could be administered according to standard practice at each participating institution following the first emetic episode or succeeding episodes, or at the request of the patient. A complete response (CR) was defined as no emetic episode and no rescue medication; complete control (CC) was defined as no emetic episode, no rescue medication, and no more than mild nausea. Efficacy for acute (024 h) and delayed (27 days) CINV was determined. Treatment was considered to be a failure (i.e. unsatisfactory therapeutic response) if a patient had at least one emetic episode or received rescue medication.
For patients participating in the pharmacokinetic portion of the study, 7 ml of whole blood were drawn into heparinized vacuum tubes 30 min before, and 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120 and 168 h after the administration of palonosetron. As only two patients received palonosetron 0.3 µg/kg, this dose level was not included in the pharmacokinetic portion of the study. Plasma was separated from whole blood by centrifugation and stored at 20°C. Plasma samples were assayed for palonosetron and its N-oxide metabolite (metabolite M9) using a validated high-pressure liquid chromatography method, with detection and quantification of each analyte via single-ion monitoring mass spectrometry. The lower limit of quantification was 0.020 ng/ml for palonosetron and 0.050 ng/ml for metabolite M9. Standard pharmacokinetic parameters were calculated by non-compartmental methods.
AEs occurring in the study were documented during the 24 h after dosing, on day 7, and on day 14. Events were assessed by the investigator for intensity and possible association with study medication. All reported events were followed until the overall clinical outcome was ascertained or until 1 month after dosing.
The primary outcome variable was the proportion of patients with a CR during the 24-h period following the start of chemotherapy. This was also evaluated each day cumulatively for 7 days following chemotherapy. Secondary measures, assessed each day for 7 days after chemotherapy initiation, included: proportion of patients experiencing CC of emesis following the start of chemotherapy; time to treatment failure (first emetic episode or rescue medication); time to first emetic episode; time to rescue medication; number of patients free from emetic episodes and with a maximum of mild nausea; number of patients free of emetic episodes with no rescue medication; number of patients free from emetic episodes with no rescue medication and no nausea; and global assessment of nausea (assessed only at 24 h).
Study drug
Palonosetron was supplied in 5 ml glass vials at a concentration of 500 µg/ml, with normal saline provided for dilution. Before the dosing protocol amendment each dose was diluted with normal saline to 10 ml; subsequent to the amendment each dose was diluted to 25 ml. The label strength for all solutions was quantified as the free base.
Statistical analyses
The primary efficacy hypothesis of the study was that there was no difference in the proportion of patients with a CR between the 0.3 or 1 µg/kg dose and any of the higher i.v. doses (3, 10, 30 and 90 µg/kg). The number of patients to be included in the study was estimated to be 115 patients (23 patients for five dose groups), assuming a responder rate of the lowest dose group of 20% and a CR rate of the higher dose group of at least 70%.
Statistical analyses were carried out using SAS software, Version 6.08 (SAS Institute, Inc., Cary, NC, USA). Significance of group differences in efficacy parameters was determined at an alpha level of 0.05 using two-sided tests; comparability among groups with respect to baseline characteristics was made at the 0.10 level. The CochranMantelHaenszel test, stratified by center, was used to test the significance of differences in CR rates between the lowest-dose group (pooled 0.3 and 1 µg/kg doses) and each of the other dose groups. Additionally, a 95% confidence interval (CI) (adjusted for multiple CIs) for the true difference in CR rates between the combined 0.3 and 1 µg/kg groups and each of the other dose groups was obtained using Dunnetts method, modified for a dichotomous response [19]. Treatment group differences for the other binary efficacy variables were analyzed similarly. Comparisons in the time-to-event distributions were assessed using the log-rank test. The Wilcoxon rank-sum test was used for comparisons of the area under the categorical NIT curve, while tests involving overall assessment of nausea were based on the CochranMantelHaenszel test stratified by center. For the CR rate at 24 h, analyses were carried out for both intention-to-treat (ITT) and per-protocol (PP) populations; the other parameters were analyzed only for the evaluable patients (PP population). Safety data were tabulated and summarized descriptively. Maximum plasma concentration (Cmax) and area under the plasma concentrationtime curve (AUC) were tested for dose-proportionality with a one-way analysis of variance controlling for dose level. Dose proportionality of plasma elimination T1/2, total body clearance (CLT), and apparent volume of distribution (Vd) was evaluated without adjusting for dose.
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Results |
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Patient characteristics are summarized in Table 1. Treatment groups were generally balanced with respect to demographic variables and medical history. There were no clinically meaningful differences between groups with regard to age, gender, race, weight, height, emetogenic chemotherapy agent, body surface area and tobacco and alcohol use within the past 6 months.
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Discussion |
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Palonosetron was well-tolerated, with no unexpected AEs reported. Only a small proportion of events (approximately 15%) were considered possibly or probably related to study medication, with the majority (>80%) of AEs considered mild-to-moderate in intensity. Importantly, incidences, frequencies, intensities and drug relationships of AEs appear to be equally distributed among the various palonosetron dose levels, with no apparent doseresponse relationships.
Over the range of doses evaluated, both Cmax and AUC0 values increased with increasing dose in a dose-proportional manner, within the range 190 µg/kg. Vd of palonosetron was large (6.82.5 l/kg) and CLT was low (1.512.23 ml/min/kg), resulting in a long plasma elimination T1/2 (>44 h). The exposure of metabolite M9 relative to palonosetron as determined by AUC ratio was low (0.0790.118). This finding, coupled with the negligible pharmacological activity of metabolite M9 (data on file), suggests that the antiemetic effect observed in patients is mainly due to palonosetron. Pharmacokinetics of palonosetron in this dose-ranging study were similar to studies in healthy volunteers [28], and are improved over other 5-HT3 antagonists due to its long T1/2, dose-proportional pharmacokinetics, large Vd, and low CLT.
In summary, palonosetron showed substantial efficacy in the prevention of CINV in patients receiving highly emetogenic cisplatin-based chemotherapy. The prolonged protection observed with palonosetron in the management of chemotherapy-induced emesis following a single i.v. dose is particularly notable and is likely related to its strong binding affinity for 5-HT3 receptors and its longer plasma elimination T1/2. The pharmacokinetics of palonosetron in this study were similar to those previously reported in phase I trials. Based on the results of this dose-ranging study, fixed palonosetron doses of 0.25 mg (3 µg/kg) and 0.75 mg (
10 µg/kg) are recommended for further evaluation, as they appear to be the lowest effective doses for the prevention of CINV in patients receiving highly emetogenic chemotherapy.
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Acknowledgements |
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Financial disclosures and potential conflicts of interest |
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FOOTNOTES |
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REFERENCES |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs 1998; 55: 173189.[ISI][Medline]
3. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999; 56: 729764.[ISI][Medline]
4. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest 2000; 18: 163173.[ISI][Medline]
5. Walton SM. Advances in use of the 5-HT3 receptor antagonists. Expert Opin Pharmacother 2000; 1: 207223.[Medline]
6. Aapro MS, Thuerlimann B, Sessa C et al. A randomized double-blind trial to compare the clinical efficacy of granisetron with metoclopramide, both combined with dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis. Ann Oncol 2003; 14: 291297.
7. Koeller JM, Aapro MS, Gralla RJ et al. Antiemetic guidelines: creating a more practical treatment approach. Support Care Cancer 2002; 10: 519522.[CrossRef][ISI][Medline]
8. Wong EHF, Clark R, Leung E et al. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors in vitro. Br J Pharmacol 1995; 114: 851859.[Abstract]
9. Miller RC, Galvan M, Gittos MW et al. Pharmacological properties of dolasetron, a potent and selective antagonist at 5-HT3 receptors. Drug Dev Res 1993; 28: 8793.[ISI]
10. Van Wijngaarden I, Tulp MTM, Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 1990; 188: 301312.[CrossRef][Medline]
11. Katayama K-I, Asano K, Haga K et al. High affinity binding of azasetron hydrochloride to 5-hydroxytryptamine3 receptors in the small intestine of rats. Jpn J Pharmacol 1997; 73: 357360.[ISI][Medline]
12. Hutt AJ, Tan SC. Drug chirality and its clinical significance. Drugs 1996; 52 (Suppl 5): 112.[ISI][Medline]
13. Eglen RM, Lee C-H, Smith WL et al. Pharmacological characterization of RS 25259197, a novel and selective 5-HT3 receptor antagonist, in vivo. Br J Pharmacol 1995; 114: 860866.[Abstract]
14. Zofran® [package insert]. Research Triangle Park, NC, USA: GlaxoSmithKline; 2001.
15. Anzemet® [package insert]. Bridgewater, NJ, USA: Aventis Pharmaceuticals; 2000.
16. Kytril® [package insert]. Nutley, NJ, USA: Roche Laboratories Inc.; 2000.
17. Serotone® [prescribing information]. Tokyo, Japan: Torii Pharmaceutical Co. Ltd; 2001.
18. Hesketh PJ, Kris MG, Grunberg SM et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15: 103109.[Abstract]
19. Piegorsch WW. Multiple comparisons for analyzing dichotomous response. Biometrics 1991; 47: 4552.[ISI][Medline]
20. Andrews PLR, Bhandari P, Davey PT et al. Are all 5-HT3 receptor antagonists the same? Eur J Cancer 1992; 28A (Suppl 1): S6S11.[Medline]
21. Falkson HC, Falkson CI, Falkson G. High versus low dose granisetron, a selective 5-HT3 antagonist, for the prevention of chemotherapy-induced nausea and vomiting. Invest New Drugs 1990; 8: 407409.[ISI][Medline]
22. Smith IE. A comparison of two dose levels of granisetron in patients receiving moderately emetogenic cytostatic chemotherapy. The Granisetron Study Group. Eur J Cancer 1990; 26 (Suppl 1): S19S23.[ISI][Medline]
23. Soukop M. A comparison of two dose levels of granisetron in patients receiving high-dose cisplatin. The Granisetron Study Group. Eur J Cancer 1990; 26 (Suppl 1): S15S19.[ISI][Medline]
24. Hesketh PJ, Gandara DR, Hesketh AM et al. Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. Support Care Cancer 1996; 4: 141146.[ISI][Medline]
25. Seynaeve C, Schuller J, Busser K et al. Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicenter, double-blind, randomised, parallel group study. Ondansetron Study Group. Br J Cancer 1992; 66: 192197.[ISI][Medline]
26. Kris MG, Grunberg SM, Gralla RJ et al. Dose-ranging evaluation of the serotonin antagonist dolasetron mesylate in patients receiving high-dose cisplatin. J Clin Oncol 1994; 12: 10451049.[Abstract]
27. Beck TM, Hesketh PJ, Madajewicz S et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting. Clin Oncol 1992; 10: 19691975.
28. Piraccini G, Stolz R, Tei M et al. Pharmacokinetic features of a novel 5-HT3-receptor antagonist: palonosetron (RS 25259-197). Proc Am Soc Clin Oncol 2001; 20: 400a (Poster 1595).