Dose Of Dolasetron Research Articles

Interventions to decrease the risk of adverse cardiac events for patients receiving chemotherapy and serotonin (5-HT3) receptor antagonists: a systematic review.

BackgroundPatients may experience nausea and vomiting when undergoing chemotherapy or surgery requiring anesthesia. Serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonists are effective antiemetics, yet may cause adverse cardiac events, such as arrhythmia. We aimed to identify interventions that mitigate the cardiac risk of 5-HT3 receptor antagonists.MethodsElectronic databases, trial registries, and references were searched. Studies on patients undergoing chemotherapy or surgery examining interventions to monitor cardiac risk of 5-HT3 receptor antagonists were included. Search results were screened and data from relevant studies were abstracted in duplicate. Risk of bias of included studies was assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) group’s risk-of-bias tool. Due to a dearth of included studies, meta-analysis was not conducted.ResultsTwo randomized clinical trials (RCT) and 1 non-randomized clinical trial (NRCT) were included after screening 7,637 titles and abstracts and 1,554 full-text articles. Intravenous administration of different dolasetron doses was examined in the NRCT, while dolasetron versus ondansetron and palonosetron versus ondansetron were examined in the RCT. Electrocardiogram (ECG) was the only intervention examined to mitigate cardiac harm. No differences in ECG evaluations were observed between dolasetron or palonosetron versus ondansetron after 15 minutes, 24 hours, and 1 week post-administration in the 2 RCTs. Four deaths were observed in one RCT, which were deemed unrelated to palonosetron or ondansetron administration. Minor increases in PR and QT intervals were observed in the NRCT for dolasetron dosages greater than 1.2 mg/kg 1–2 hours post-administration, but were deemed not clinically relevant.ConclusionsECG monitoring of chemotherapy patients administered with 5-HT3 receptor antagonists did not reveal clinically significant differences in arrhythmia between the medications at the examined time periods. The usefulness of ECG to monitor chemotherapy patients administered with 5-HT3 receptor antagonists remains unclear, as all patients received ECG monitoring.Trial registrationPROSPERO registry number: CRD42013003565Electronic supplementary materialThe online version of this article (doi:10.1186/2050-6511-16-1) contains supplementary material, which is available to authorized users.

Chemotherapy-induced nausea and vomiting: ESMO Clinical Recommendations for prophylaxis

Chemotherapy-induced nausea and vomiting: ESMO Clinical Recommendations for prophylaxis

Palonosetron: A Second-Generation 5-Hydroxytryptamine Receptor Antagonist

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine (5-HT)3 receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a clinical problem. A new agent, palonosetron, has recently been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. In a single dosing study, palonosetron was highly effective in controlling CINV compared with a single dose of dolasetron or ondansetron in patients receiving moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone demonstrated control of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron appeared to be as effective in subsequent courses of chemotherapy compared with the initial course of chemotherapy. There were no clinically relevant differences seen among palonosetron, ondansetron or dolasetron in laboratory, electrocardiographic or vital-sign changes, and adverse reactions reported in the clinical trials were the most common reactions reported for the 5-HT3 receptor antagonist class. Recent studies using palonosetron-based anti-emetic combinations in moderately and highly emetogenic chemotherapy, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Future studies may consider the use of palonosetron with current and other new agents and in other clinical settings, such as bone marrow transplantation and radiation therapy.

5‐hydroxytryptamine type‐3 receptor antagonists for chemotherapy‐induced and radiotherapy‐induced nausea and emesis

Nausea and emesis as a consequence of chemotherapy or radiotherapy can have an adverse effect on patients' quality of life during cancer treatment and may last for > 5 days after administration. Guidelines suggest that, used at appropriate doses, the 5-hydroxytryptamine type-3 (5-HT3) receptor antagonists--which are considered the antiemetic "gold standard" when they are administered in combination with corticosteroids--demonstrate equivalent efficacy and safety. However, due to financial considerations, these agents often are used at lower doses than recommended. A literature review of relevant publications pertaining to the control of chemotherapy-induced nausea and emesis and dosing issues of the 5-HT3 receptor antagonists was undertaken to provide a comprehensive review of dosing issues relevant to the 5-HT3 receptor antagonists. The issue of "down dosing" was particularly pertinent because of the nature of the 5-HT3 receptor antagonist dose-response curve: A steep dose-response profile within a narrow dose range suggests that antiemetic control will be lost suddenly after dose deescalation. However, the array of predisposing and confounding patient factors indicates that it is unlikely that a loss of antiemetic control will be apparent across a population; rather, individuals will experience loss of control as the dose is reduced below threshold. Of the 4 5-HT3 receptor antagonists currently licensed in the United States (granisetron, ondansetron, dolasetron, and palonosetron), ondansetron is used sometimes at lower than optimal doses, and there is evidence to suggest that even the approved oral dose of dolasetron may be suboptimal. Suboptimal dosing not only will be detrimental to patients' quality of life but, ultimately, will prove counterproductive in terms of hospital resources, and it will add to the already significant socioeconomic burden associated with cancer therapy. Therefore, the dose of antiemetic agent administered should be sufficiently high to ensure good emesis control across the whole patient population.

A Randomized, Multicenter, Open-Label Comparison of the Antiemetic Efficacy of Dolasetron Versus Ondansetron for the Prevention of Nausea and Vomiting During High-Dose Myeloablative Chemotherapy

This study assessed the efficacy and safety of dolasetron compared with ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy followed by peripheral blood stem cell support. Twenty centers randomized 197 patients to receive dolasetron 100 mg intravenously (I.V.) followed 8–12 hours later by a single oral dose of dolasetron 100 mg or ondansetron 32 mg I.V., followed 8-12 hours later by a single oral dose of ondansetron 8 mg during high-dose chemotherapy (HDC) regimens for breast cancer (n = 96; 48.7%), non-Hodgkin's lymphoma (n = 83; 42.1%), or Hodgkin's disease (n = 18; 9.1%). All patients received a daily I.V. bolus of dexamethasone 10 mg with study antiemetic agents and a continuous infusion of diphenhydramine, lorazepam, and dexamethasone (ie, BAD pump) throughout the course of the study, with patient-controlled on-demand bolus doses as needed. After completing a daily diary of emetic episodes and rescue medication use, 164 of 197 patients were evaluable. Total plus complete responses (no emesis, no nausea, no rescue) over the entire study period were achieved in 45.7% and 46.9% of patients on the dolasetron and ondansetron arms, respectively. Dolasetron and ondansetron were well-tolerated. This study demonstrates that dolasetron and ondansetron are equally safe and effective in the prevention of nausea and vomiting associated with HDC (P = 0.955).

Timing of administration of dolasetron affects dose necessary to prevent postoperative nausea and vomiting

Study objective To determine if the timing of administration affects the dose of dolasetron necessary to prevent postoperative nausea and vomiting (PONV). Design Pooled data from 8 randomized, multicenter, double-blind, placebo-controlled studies with common endpoints. Setting University hospital. Patients A total of 4,587 ASA physical status I, II, and III patients, including 4,124 females undergoing primarily gynecologic procedures and 463 males undergoing various procedures (i.e., thyroidectomy or orthopedic, ophthalmologic, urologic, ENT, or laparoscopic surgery). Interventions Balanced general anesthesia was used during all procedures. Patients received a dose of dolasetron either for prevention of PONV (25 or 50 mg IV at induction; 25, 50, 100, or 200 mg orally 1 to 2 hours pre-induction; or 12.5, 25, 50, or 100 mg IV at end of anesthesia) or for treatment of PONV (12.5, 25, 50, or 100 mg IV). One PONV prevention study had an ondansetron (comparator) group. Measurements Outcome measures over a 24-hour study period included complete response (defined as no vomiting/retching and no need for rescue medication), percentage of patients without nausea [defined as nausea visual analog scale (VAS) score < 5 mm], and maximum nausea according to VAS score. Main results A 12.5-mg IV dose of dolasetron resulted in a complete response rate that was statistically significantly higher than placebo and comparable to higher dolasetron doses (25 mg to 100 mg IV) when administered either near the end of anesthesia for prevention of PONV or at the onset of symptoms for treatment of PONV. In contrast, when administered at induction of anesthesia, a statistically significant treatment response was observed with dolasetron 50 mg IV, but not at a lower dose. Conclusions When dosed near the end of anesthesia, a 12.5 mg IV dose of dolasetron was comparable to higher doses administered at or before induction of anesthesia.

Open-label, Randomized Comparison of the Efficacy of Intravenous Dolasetron Mesylate and Ondansetron in the Prevention of Acute and Delayed Cisplatin-induced Emesis in Cancer Patients

The aim of this study is to compare the antiemetic efficacy and tolerability of intravenous dolasetron mesylate and ondansetron in the prevention of acute and delayed emesis. From April 2002 through October 2002, a total of 112 patients receiving cisplatin- based combination chemotherapy were randomized to receive a single i.v. dose of dolasetron 100 mg or ondansetron 8 mg, 30 minutes before the initiation of chemotherapy. In the ondansetron group, two additional doses of ondansetron 8 mg were given at intervals of 2 to 4 hours. To prevent delayed emesis, dolasetron 200 mg p.o. daily or ondansetron 8 mg p.o. bid was administered from the 2(nd) days to a maximum of 5 days. The primary end point was the proportion of patients that experienced no emetic episodes and required no rescue medication (complete response, CR) during the 24 hours (acute period) and during Day 2 to Day 5+/-2 days (delayed period), after chemotherapy. The secondary end points included the incidence and severity of emesis. 105 patients were evaluable for efficacy. CR rates during the acute period were 36.0% for a single dose of dolasetron 100 mg, and 43.6% for three doses of ondansetron 8 mg. CR rates during the delayed period were 8.0% and 10.9%, respectively. There was no significant difference in the efficacy between the two groups. Adverse effects were mostly mild to moderate and not related to study medication. A single i.v. dose of dolasetron 100 mg is as effective as three i.v. doses of ondansetron 8 mg in preventing acute and delayed emesis after cisplatin-based chemotherapy, with a comparable safety profile.

Pooled analysis of three large clinical trials to determine the optimal dose of Dolasetron Mesylate needed to prevent postoperative nausea and vomiting

Study Objective: To identify the maximally effective dolasetron dose (i.e., maximum efficacy with minimum adverse events) for prevention of postoperative nausea and vomiting (PONV) using the statistical power generated in a pooled patient sample from three large, nearly identical clinical trials. Design: Three randomized, multicenter, placebo-controlled, double-blinded trials. Setting: Trials 1, 2, and 3 enrolled patients at 10, 25, and 17 hospitals and/or surgical centers, respectively. Patients: A total of 1,946 ASA physical status I, II, and III patients. Trials 1 and 2 enrolled only female patients (n = 916) undergoing gynecologic surgery. Trial three enrolled 722 females (∼70% gynecologic surgeries) and 308 males (∼46% orthopedic surgeries) undergoing a variety of surgical procedures. Interventions: All surgical procedures used balanced general anesthesia. Patients received 12.5, 25, 50, or 100 mg of the antiemetic, dolasetron, near the end of anesthesia. Measurements and Main Results: Efficacy endpoints were identical and measured for 24 hours: complete response (no vomiting or rescue medication) and maximum nausea, reported using a 100-mm visual analog scale (VAS). Safety was assessed using adverse event reports, laboratory and electrocardiographic data, and vital signs. All four dolasetron doses produced significant increases in complete response and decreases in maximum VAS nausea compared with placebo (p < 0.01). No increased efficacy was observed with dolasetron doses higher than 12.5 mg. Safety was similar between each dolasetron dose and placebo. Conclusion: Dolasetron 12.5 mg, given near the end of anesthesia, is the maximally effective dose studied for preventing postoperative nausea and vomiting.

Safety, tolerability, antiemetic efficacy, and pharmacokinetics of oral dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.

The safety, antiemetic efficacy, and pharmacokinetics of single oral doses of dolasetron, a new highly selective 5-HT3 receptor antagonist, were evaluated in children with cancer undergoing treatment with moderately to highly emetogenic chemotherapy. A total of 32 children, ages 3 to 18 years, were enrolled in a nonrandomized, multicenter, open-label, dose-escalation study. Three oral dose levels (0.6, 1.2, or 1.8 mg/kg) were studied. Safety, efficacy, and pharmacokinetic parameters were assessed over 24 hours at each dosage level. The most effective dose was 1.8 mg/kg; 60% of the patients achieved a complete or major response (< or =2 emetic episodes in 24 hours). A complete response was achieved in 3 of 9 patients (33%) who received 0.6 mg/kg, 4 of 13 (31%) patients who received 1.2 mg/kg, and 5 of 10 (50%) patients who received 1.8 mg/kg of dolasetron. Overall, dolasetron was well tolerated. Adverse events were mild and similar to those reported in adults. Peak plasma concentrations (Cmax) of dolasetron's active reduced metabolite, MDL 74,156, were dose proportional and occurred, on the average, within 1 hour of oral administration. The half-life (t1/2) in plasma was approximately 6 hours for all dose levels, and the mean clearance (CLapp) was unrelated to dose. Oral dolasetron is safe and effective in reducing chemotherapy-induced nausea and vomiting, particularly at the 1.8-mg/kg dose level. These results support further evaluation of oral dolasetron in larger randomized clinical trials in the pediatric cancer population.

Rationale for the use of a single fixed intravenous dolasetron dose for the prevention of cisplatin-induced nausea and vomiting. Pooled analysis of 14 clinical trials.

Dolasetron mesilate is a selective 5-HT3 receptor antagonist that prevents chemotherapy-induced and postoperative nausea and vomiting. For the majority of patients in intravenous dolasetron trials for chemotherapy-induced nausea and vomiting, dosing has been based on body weight (mg/kg). The approved weight-based dose is 1.8 mg/kg based on results of controlled clinical trials. However, trials of dolasetron evaluating oral doses for prevention of chemotherapy-induced emesis, and intravenous doses for prevention and treatment of postoperative emesis have used a fixed milligram dose. To identify an appropriate intravenous fixed milligram dose for the prevention of chemotherapy-induced nausea and vomiting, this analysis was performed to derive efficacy results for fixed milligram doses from pooled results obtained with dosing based on body weight. Intravenous dolasetron doses for 1,598 patients treated on a mg/kg basis (0.3, 0.6, 1.2, 1.8, 2.4, 3.0 and 5.0 mg/kg) in 14 clinical trials were converted to fixed milligram doses based on weight. Fixed-dose groups were established at doses of 50, 75, 100, 125, 150, and 200 mg. Doses less than or equal to the midpoint between two dose groups were included in the lower dose group. Pooled results showed that the 100 mg intravenous dolasetron dose group (who received actual doses of 88-112 mg) produced the highest rate (53%) of complete response (0 emetic episodes and no rescue medication in the 24-h period following initiation of chemotherapy).

Oral Dolasetron Mesylate for Prevention of Postoperative Nausea and Vomiting: A Multicenter, Double-Blind, Placebo-Controlled Study

Study Objective: To examine the safety and effectiveness of a range of single oral doses of dolasetron mesylate for the prevention of postoperative nausea and vomiting. Design: Randomized, double-blind, placebo-controlled trial. Setting: 32 hospitals. Patients: 789 female ASA physical status I, II, and III patients, ages 18 to 60 years, weighing between 45 and 100 kg, scheduled for major gynecologic surgery (including abdominal hysterectomy, gynecologic laparotomy, or vaginal hysterectomy) with general anesthesia. Interventions: 25, 50, 100, or 200 mg oral doses of dolasetron mesylate or placebo were administered 1 to 2 hours before induction of anesthesia. Efficacy was assessed for 24 hours postrecovery by measuring complete response (no emetic episodes, no rescue medication), total response (complete response with no nausea), time to first emetic episode or rescue, and patient visual analog scale evaluations of nausea severity and satisfaction with antiemetic therapy. Measurements and Main Results: Complete response rates for the 50, 100, and 200 mg dose groups were statistically greater than placebo (p ≤ 0.018). Likewise, total response rates were statistically greater in the 50, 100, and 200 mg dose groups than in the placebo group (p = 0.012). Percentage of patients with no nausea and patient satisfaction scores were significantly higher for each dolasetron dose group than placebo (p ≤ 0.047 and p ≤ 0.004, respectively). Efficacy peaked at the 50 mg dose. The incidence of adverse events was similar in the placebo (30.1%) and dolasetron groups (29.4%). Headache was the most frequent treatment-related adverse event, with 2% to 5% incidence across groups. Incidence of adverse events did not increase with increasing dolasetron doses. Dose-related decreases in blood pressure at acute time points were not clinically significant. Conclusion: Single oral doses of dolasetron, administered 1 to 2 hours before induction of anesthesia, are safe and effective for preventing postoperative nausea and vomiting in this patient sample. Maximal antiemetic response was seen with the 50 mg oral dolasetron dose.

Treatment of Postoperative Nausea and Vomiting with Single Intravenous Doses of Dolasetron Mesylate

This study was conducted to determine the efficacy and safety of four intravenous (IV) doses of dolasetron, an investigational 5-HT3 receptor antagonist, for the treatment of postoperative nausea and/or vomiting (PONV) after outpatient surgery under general anesthesia. This multicenter, randomized, double-blind trial compared the antiemetic efficacy of 12.5, 25, 50, or 100 mg IV dolasetron with placebo over 24 h using complete response (no emetic episodes and no rescue medication), time to first emetic episode or rescue medication, and patient nausea and satisfaction with antiemetic therapy as rated by visual analog scale (VAS). Of 1557 patients enrolled, 620 patients were eligible for treatment. Complete response rates for all dolasetron doses-12.5 mg (35%), 25 mg (28%), 50 mg (29%), and 100 mg (29%)-were significantly more effective than placebo (11%, P < 0.05). There was a significant gender interaction for complete response (P < 0.01). Of the patients in the 25-mg and 100-mg dose groups, 12% and 13%, respectively, experienced no nausea (VAS score < 5 mm) versus 5% in the placebo group (P < 0.05). There were no clinically relevant changes in vital signs or laboratory values and no trends with dose for adverse events. Dolasetron is effective for treating PONV and has an adverse event profile similar to that of placebo. The 12.5-mg dose was as effective as larger doses for complete response. Implications: Nausea and vomiting are common problems for postsurgical patients. In this study of 620 patients undergoing surgery, a 12.5-mg dose of intravenous dolasetron, a new serotonin-receptor blocker, was significantly more effective than placebo in treating established postoperative nausea and vomiting. Dolasetron 12.5 mg was as safe as placebo. (Anesth Analg 1997;85:546-52)

Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery.

Dolasetron (dolasetron mesilate) is a pseudopelletierine-derived 5-HT3 antagonist which has recently become available for clinical use. It is rapidly converted in vivo to its active major metabolite, hydrodolasetron, which appears to be largely responsible for its pharmacological activity. In clinical trials, single intravenous or oral doses of dolasetron were effective in preventing acute chemotherapy-induced nausea and vomiting (CINV). Intravenous doses of 1.8 mg/kg achieved complete suppression of vomiting in approximately 50% of patients receiving highly emetogenic cisplatin-containing chemotherapy and in approximately 60 to 80% of patients receiving moderately emetogenic chemotherapy. In the latter setting, oral doses of 200 mg achieved similar response rates. In comparative studies, intravenous dolasetron 1.8 mg/kg was as effective as intravenous granisetron 3 mg or ondansetron 32 mg after highly emetogenic chemotherapy, and oral dolasetron 200 mg was equivalent to multiple oral doses of ondansetron (3 or 4 doses of 8 mg) after moderately emetogenic chemotherapy. Dolasetron 1.8 mg/kg was superior to metoclopramide in preventing emesis induced by high dose cisplatin or by moderately emetogenic chemotherapy in high risk subgroups. Dolasetron has also shown efficacy in preventing radiotherapy-induced nausea and vomiting (RINV) in preliminary studies. Single intravenous or oral dolasetron doses ranging from 12.5 to 100 mg and 25 to 200 mg, respectively, were significantly more effective than placebo in preventing postoperative nausea and vomiting (PONV) in female surgical patients. A 50 mg intravenous dose was as effective in preventing PONV as ondansetron 4 mg in a mixed-gender group. Intravenously administered dolasetron was also effective in treating established PONV, although complete suppression of vomiting was achieved in < 40% of patients. Dolasetron has a tolerability profile characteristic of this class of compounds, with headache, dizziness and diarrhoea being the most commonly occurring adverse events in clinical trials. Diarrhoea is not thought to be related to dolasetron administration, being experienced mostly by patients receiving chemotherapy. Dolasetron and other 5-HT3 receptor antagonists have been associated with minor changes in ECG intervals, but these generally do not appear to be clinically important. Thus, available evidence suggests that dolasetron will provide an alternative to other 5-HT3 receptor antagonists for the management of CINV and PONV. Further studies are required to determine whether it offers any advantages over other agents in these settings and to determine the optimum dosage for preventing RINV.

Randomized, double blind, dose‐response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy

Randomized, double blind, dose‐response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy

This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.

A Double-Blind, Randomized Study of Two Different Dosage Regimens of Intravenous Dolasetron in Patients Receiving High-Dose Cisplatin Chemotherapy

This study compared the antiemetic efficacy and safety of two different intravenous (IV) dolasetron dosing regimens in patients receiving their first course of high-dose (≧80 mg/m2) cisplatin. Of 30 patients enrolled, 14 received a single IV dolasetron dose (0.6 mg/kg) before cisplatin and 16 received a multiple IV dose regimen (0.6 mg/kg x 3) given before and after cisplatin. Complete plus major responses were achieved by 71% (10/14) of patients who received single-dose dolasetron and by 50% (8/16) of those who received the multiple-dose regimen. Forty-three percent (6/14) of patients who received the single dose liad a complete response compared with 25% (4/16) who received multiple doses. Multiple doses resulted in less nausea at 24 hr following cisplatin; however, differences were not statistically significant. Both regimens were well tolerated, with mild headache (33%) and diarrhea (13%) the most common adverse events. This study demonstrated that a single 0.6-mg/kg dose of dolasetron given before chemotherapy provides equivalent antiemetic efficacy to three 0.6-mg/kg doses given before and after high-dose cisplatin chemotherapy; thus, there was no additional antiemetic benefit by using the multiple-dose regimen.

Timing of administration of dolasetron affects dose necessary to prevent post-operative nausea and vomiting (PONV)

Administration of a 5-HT3 receptor antagonist before induction of anaesthesia is based on the hypothesis that blocking the receptors is necessary prior to the emetogenic stimuli of anaesthesia and surgery. To test this hypothesis, we pooled eight clinical trials of oral or i.v. dolestron mesilate (DM) administered at four different intervals, pre- and post-surgery. DM is a new 5-HT3 receptor antagonist, shown to prevent and treat PONV [1,2]. The eight pooled trials were designed identically (double-blind, placebo-controlled, randomized), had similar enrolment criteria (ASA physical status 1–3 patients), and used general balanced anaesthesia. Six trials (four i.v. and two oral) studied doses of DM for prevention of PONV. (One of the i.v. prevention trials used ondansetron (OND) as an active comparator.) Two trials assessed doses of DM for the treatment of established PONV in patients with moderate to severe nausea lasting >5 min and/or vomiting, within 2 h of awakening. The table lists number of trials, doses studied, and timing of DM or OND administration. Complete response (CR: no vomiting/retching and no rescue medication over a 24 h study period) was the primary endpoint. When administered before or at induction of anaesthesia, the 50 mg dose was significantly more effective in preventing PONV than placebo and equivalent to OND (4 mg). The 25 mg DM dose was ineffective compared with placebo. When administered near the end of anaesthesia, the 12.5 mg DM dose produced significantly higher CR rates than placebo. CR rates with the higher doses were equivalent to the 12.5 mg dose. For treatment of established PONV, DM 12.5 mg was statistically superior to placebo for CR. Again, no increases in efficacy were recorded with higher DM doses (Table 10).Table 10: abstract 32).We conclude that blocking 5-HT3 receptors prior to the emetogenic stimuli of anaesthesia and surgery is not required to prevent PONV. When dosed near the end of anaesthesia, a lower dose of dolasetron (12.5 mg) was as efficacious as 50 mg DM administered at or before induction of anaesthesia. The significant efficacy of DM 12.5 mg in treating established PONV further corroborate this finding. All doses were safely administered and well tolerated across the eight trials.

Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide

Selective 5-HT3 antagonists have proven to be safe and effective for the prevention of chemotherapy-induced nausea and vomiting. Dolasetron is a new highly selective addition to this class of antiemetics that has been shown to have significant antiemetic activity in patients receiving cisplatin-containing regimens. This pilot study was designed to evaluate the antiemetic efficacy of dolasetron in cancer patients receiving doxorubicin and/or cyclophosphamide. This study used an open-label, non-randomized design to evaluate the efficacy and safety of intravenous dolasetron in the prevention of emesis in patients receiving doxorubicin (25-75 mg/m2) and/or cyclophosphamide (400-1200 mg/m2). Sixty-nine patients received a single, intravenous dose of dolasetron over 15-20 min beginning 30 min prior to the start of chemotherapy. Dose levels of dolasetron studied were: 0.3, 0.6, 1.2, 1.8 and 2.4 mg/kg. Patients were monitored for emesis, nausea and adverse events for 24h after the start of chemotherapy. Overall, 61% of patients experienced complete control of emesis. No significant trend towards increased antiemetic efficacy (P = 0.076) or nausea control with increasing dolasetron dose was noted, although the power to detect significant differences was limited by the small number of patients on the 0.3-mg/kg and 2.4-mg/kg dose levels. Age, gender, and type of chemotherapy were significant predictors of complete antiemetic control. Adverse events were generally mild and included headache, chills, lightheadedness, fever, diarrhea, dizziness, and asymptomatic prolongation of ECG intervals. Intravenous dolasetron is safe and effective in the prevention of emesis induced by doxorubicin and/or cyclophosphamide.

1227 Dose-response trial across four oral doses of dolasetron (DM) for emesis prevention after moderately emetogenic chemotherapy (CT)

This double-blind multicenter trial studied four oral doses of OM for antiemetic effectiveness in 319 predominately CT-naive cancer patients, receiving IV CT. Patients were randomized to one of four treatments: 25, 50, 100, or 200 mg of DM, 30 minutes prior to CT with doxorubicin (in combination: 25–75 mg/m2 or alone: ≥ 40 mg/m2) and/or cyclophosphamide (500–1200 mg/m2). Efficacy was compared across doses using complete response (CR: no emetic episodes [EE] and no escape medication [EM]); CR + major response (CMR: 1–2 EE and no EM); patients assessment of nausea < 5 mm = no nausea) and satisfaction with antiemetic therapy via a 100 mm visual analog scale (VAS). At 24 hours, statistically significant linear trends (P < 0.0001) were detected across the 25, 50, 100, and 200 mg doses of DM, respectively, for CR (31%, 34%, 49%, and 46%), for CMR (28%, 43%, 52%, 56%), and for CR + no nausea (20.5%, 26.5%, 37.5%, 39.7%). Lineartrends with dose were also statistically significant for patient assessment of nausea (P < 0.0006) and general satisfaction (P < 0.0009). No significant dose related trends in the incidence of headache or elevated transaminases were detected. Single oral doses of DM are effective in preventing emesis in cancer patients with excellent safety and efficacy recorded with both the 100 and 200 mg doses of dolasetron. This double-blind multicenter trial studied four oral doses of OM for antiemetic effectiveness in 319 predominately CT-naive cancer patients, receiving IV CT. Patients were randomized to one of four treatments: 25, 50, 100, or 200 mg of DM, 30 minutes prior to CT with doxorubicin (in combination: 25–75 mg/m2 or alone: ≥ 40 mg/m2) and/or cyclophosphamide (500–1200 mg/m2). Efficacy was compared across doses using complete response (CR: no emetic episodes [EE] and no escape medication [EM]); CR + major response (CMR: 1–2 EE and no EM); patients assessment of nausea < 5 mm = no nausea) and satisfaction with antiemetic therapy via a 100 mm visual analog scale (VAS). At 24 hours, statistically significant linear trends (P < 0.0001) were detected across the 25, 50, 100, and 200 mg doses of DM, respectively, for CR (31%, 34%, 49%, and 46%), for CMR (28%, 43%, 52%, 56%), and for CR + no nausea (20.5%, 26.5%, 37.5%, 39.7%). Lineartrends with dose were also statistically significant for patient assessment of nausea (P < 0.0006) and general satisfaction (P < 0.0009). No significant dose related trends in the incidence of headache or elevated transaminases were detected. Single oral doses of DM are effective in preventing emesis in cancer patients with excellent safety and efficacy recorded with both the 100 and 200 mg doses of dolasetron.

Pharmacology of the human metabolites of dolasetron, an antiemetic 5‐HT3 receptor antagonist

AbstractDolasetron mesylate (MDL 73, 147EF) is a novel 5‐HT3 receptor antagonist under development as an anti‐emetic. Dolasetron undergoes rapid and extensive metabolism to form a major metabolite, MDL 74,156; the metabolism is stereoselective, with the [+]‐enantiomer (MDL 73,405) predominant. MDL 74,156 is also hydroxylated to form MDL 102, 382 (5′‐OH metabolite) and MDL 73,492 (6′‐OH metabolite). The present study evaluated the pharmacological properties of dolasetron and its human metabolites in vitro and following oral and intravenous administration in rats and compared the antiemetic effects of dolasetron and ondansetron in dogs. Each of the metabolites had high affinity at and was selective for 5‐HT3 receptors. In anesthetized rats, the 5‐HT‐mediated von Bezold‐Jarisch reflex was inhibited by 1 mg/kg oral doses of either dolasetron (3.1 μmol/kg), ondansetron (3.4 μmol/kg), granisetron (3.2 μmol/kg), or tropisetron (3.5 μmol/kg) and by intravenous doses of dolasetron and ondansetron. Dolasetron had a significantly longer duration of action than ondansetron. In addition, the metabolites MDL 73,405, MDL 102,382, and MDL 73,492 exhibited significant 5‐HT3 receptor antagonist activity following intravenous administration, but only MDL 73,405 exhibited significant activity following oral administration. Both dolasetron mesylate and ondansetron reduced the number of emetic episodes and increased the time to first emetic event in cisplatin‐treated dogs. The clinical effects and duration of action observed following administration of dolasetron mesylate to humans are likely due mainly to MDL 73,405 (the [+]‐enantiomer of MDL 74,156). © 1995 Wiley‐Liss, Inc.