Integrated acidity and rabeprazole pharmacology.

BACKGROUND: Integrated gastric and oesophageal acidity can be calculated from measurements of gastric and oesophageal pH and used to quantify gastric and oesophageal acidity over time. Rabeprazole is a new proton pump inhibitor that is effective in treating gastro-oesophageal reflux disease (GERD). AIM: To use measurement of integrated gastric and oesophageal acidity to determine the onset, duration and overall effect of rabeprazole in subjects with GERD. METHODS: Subjects with GERD were required to have oesophageal pH less-than-or-equal 4 for at least 10% of a 24-h recording. Effects of 20 mg rabeprazole on 24-h gastric and oesophageal pH were measured on days 1 and 7 of dosing. Integrated gastric and oesophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h record. RESULTS: At steady-state, 20 mg rabeprazole inhibited gastric acidity by 89% and oesophageal acidity by 95%. The first dose of rabeprazole inhibited gastric and oesophageal acidity by at least 70% of the steady-state effect. Oesophageal acidity could be divided into monophasic and biphasic patterns, and rabeprazole had different effects on oesophageal and gastric acidity in these two GERD subpopulations. The onset of action of the first dose of rabeprazole on gastric acidity was 4 h and on oesophageal acidity was 4 h in monophasic subjects and 7 h in biphasic subjects. Integrated acidity was more sensitive than time pH less-than-or-equal 4 in measuring the inhibitory actions of rabeprazole. CONCLUSIONS: Integrated gastric and oesophageal acidity are quantitative measurements that provide useful and novel information regarding the pathophysiology of GERD as well as the impact of antisecretory agents such as rabeprazole.

Dolasetron for the prevention of postoperative nausea and vomiting following outpatient surgery with general anaesthesia: a randomized, placebo-controlled study. The Dolasetron PONV Prevention Study Group.

In a multicentre, randomized, double-blind, placebo-controlled dose-ranging study, 1030 patients undergoing outpatient surgery with general anaesthesia received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The principal outcome measure was the proportion of patients who were free of emesis or rescue medication for the 24-h period after the study drug was given; the subsidiary outcome measure was survival time without rescue medication. Effects on nausea were quantified using a visual analogue scale. Compared with placebo, a complete response was significantly higher when all four dolasetron doses were combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron provided maximum clinical benefit (effectiveness compared with adverse events), with no additional benefit in complete response rates or nausea visual analogue scale scores at higher doses. No significant differences were observed in complete response for any dolasetron dose in males compared with placebo. The majority of adverse events reported were mild or moderate. Dolasetron provided well-tolerated, safe, and effective prophylaxis for post-operative nausea and vomiting with maximum effectiveness observed at a dose of 12.5 mg.

Pharmacokinetics of intravenous dolasetron in cancer patients receiving high-dose cisplatin-containing chemotherapy.

Dolasetron mesylate (MDL 73,147, Anzemet, Hoechst Marion Roussel, Kansas City, MO) is a 5-HT ( 3 ) receptor antagonist undergoing clinical evaluation as an antiemetic agent. Dolasetron is rapidly metabolized to form hydrodolasetron (MDL 74,156). The pharmacokinetics of hydrodolasetron were studied after administration of a single intravenous infusion of 0.6 mg/kg (group I) or 1.8 mg/kg (group II) in 21 cancer patients participating in a randomized, double-blind, parallel-group, multicenter trial of the drug in patients receiving their first course of high-dose (>/=75 mg/m ( 2 ) ) cisplatin-containing chemotherapy. The intent of this study was to obtain preliminary data on the pharmacokinetics of the active metabolite, hydrodolasetron, in cancer patients. The reduced metabolite, hydrodolasetron, was formed rapidly with peak plasma concentrations (group I, mean = 128.6 ng/mL; group II, mean = 505.3 ng/mL) occurring at or shortly after the end of the infusion. Plasma concentrations of hydrodolasetron remained quantifiable for up to 24 hours. Increases in peak plasma concentrations and AUC of hydrodolasetron were proportional to dose, suggesting linear pharmacokinetics over this dose range. Apparent clearance, apparent volume of distribution, elimination rate, and terminal elimination half-life of the reduced metabolite were similar at both doses. The results support a pharmacokinetic basis for the prolonged duration of antiemetic efficacy after a single intravenous dose.

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1.

In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC0-infinity)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33%) and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (C1), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine (> 86%). Dolasetron was well tolerated following both oral and intravenous administration.

Single- and multiple-dose pharmacokinetics of oral dolasetron and its active metabolites in healthy volunteers: part 2.

The single- and multiple-dose pharmacokinetics and dose-proportionality of oral dolasetron and its active metabolites over the therapeutic dose range was investigated in 18 healthy men. In an open-label, randomized, complete three-way crossover design, each subject received three separate doses: 50, 100, and 200 mg doses of dolasetron mesylate solution given orally. Each dose was administered on the morning of Days 1 and 3-7 during each of the three treatment periods. Serial blood and urine samples were collected for 48 h after the first and last doses. Blood was analysed for dolasetron and hydrodolasetron concentrations; urine was analysed for dolasetron, the R(+) and S(-)-enantiomers of hydrodolasetron, and the 5'-hydroxy and 6'-hydroxy metabolites of hydrodolasetron. Dolasetron was rarely detected in plasma. Hydrodolasetron was formed rapidly, with a time to maximum concentration (t(max)) of less than 1 h. Steady-state conditions for hydrodolasetron were reached 2-3 days after starting once-daily dosing. Although statistical significance was found for hydrodolasetron AUC(0->infinity) and C(max) between dose groups after both single and multiple doses of dolasetron, the differences were small and unlikely to be of clinical significance. About 17-22% of the dose was excreted in urine as hydrodolasetron, with the majority (> 83%) as the R(+) enantiomer.

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. The Oral Dolasetron PONV Prevention Study Group.

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 < or = 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 < or = 0.047 and p < or = 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: a multicenter trial. Dolasetron Mesylate PONV Treatment Study Group.

UNLABELLED: This study was conducted to determine the efficacy and safety of four intravenous (I.V.) 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 I.V. 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.

Intravenous dolasetron mesilate in the prevention of postoperative nausea and vomiting in females undergoing gynecological surgery.

STUDY OBJECTIVE: To evaluate a range of doses of intravenous (i.v.) dolasetron mesilate, in preventing postoperative nausea and vomiting (PONV). DESIGN: Double-blind, placebo-controlled, randomized, multicenter trial. SETTING: Ten hospitals and/or surgical centers. PATIENTS: 281 women undergoing gynecologic surgery with general anesthesia. INTERVENTIONS: Patients received one of four single, i.v. doses of dolasetron mesilate (12.5 mg, 25 mg, 50 mg, and 100 mg) or placebo administered following cessation of anesthesia. MEASUREMENTS AND MAIN RESULTS: Patients were monitored for 24 hours following study drug administration. The antiemetic efficacy of each dolasetron mesilate dose was evaluated by recording the number and timing of emetic episodes, and the effects on nausea were assessed by use of visual analog scales (VAS). Safety was assessed by adverse event reports, clinical laboratory tests, electrocardiographic (ECG) measurements, and monitoring vital signs. Complete responses (patients with no emetic episodes and no escape antiemetic medication requirements in 24 hours) were achieved by 54% in the 12.5-mg, 67% in the 25-mg, and 59% in both the 50-mg and 100-mg dolasetron mesilate dose groups, and by 43% in the placebo group. Nausea VAS assessments demonstrated that dolasetron-treated patients were significantly (p = 0.048) more likely to report no nausea (VAS score < 5 mm) than those in the placebo group. Adverse events reported generally were mild in intensity, and there were no clinically significant changes in laboratory tests, vital signs, or ECG parameters. CONCLUSIONS: Dolasetron was effective and well tolerated for the prevention of PONV in female patients undergoing gynecologic surgery with general anesthesia.

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.

Intravenous dolasetron mesilate ameliorates postoperative nausea and vomiting.

PURPOSE: To compare the efficacy, safety, and tolerability of dolasetron mesilate with placebo for the treatment of postoperative nausea and vomiting (PONV). METHODS: In a randomized, multicentre, double-blind, placebo-controlled study 337 adult patients undergoing surgery with general anaesthesia received one of four single, doses of dolasetron mesilate iv (12.5, 25, 50, or 100 mg) or placebo. Study medication was administered postoperatively when the patient reported nausea lasting 10 min or when one emetic episode occurred within two hours of the patient's arrival in the recovery room. Efficacy was assessed by the investigators over the 24-hr study period by recording the number and timing of emetic episodes, the severity of nausea, the timing of administration of escape antiemetic medications, and patients' and investigators' satisfaction with antiemetic therapy. RESULTS: The study sample was predominately women, and the surgical procedures were primarily gynaecological. All dolasetron mesilate doses produced higher complete response rates than placebo (P < 0.05). Only approximately one-third of dolasetron patients required escape antiemetic medication compared with more than 50% of patients in the placebo group. Both patient and physician satisfaction with dolasetron treatment was high. The most common adverse event was mild or moderate headache for both placebo-treated patients and dolasetron-treated patients. Clinical laboratory results were unremarkable. CONCLUSION: Single doses of dolasetron mesilate iv, given after the first episode of PONV, were both effective and safe in this adult patient population.

Intravenous dolasetron for the prevention of postoperative nausea and vomiting after outpatient laparoscopic gynecologic surgery.

The newer 5-hydroxytryptamine type 3 (5-HT3) antagonists are sometimes considered for routine prophylaxis of postoperative nausea and vomiting (PONV) in high-risk patients. This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and safety of three single intravenous (IV) doses of dolasetron mesylate salt (12.5, 25, or 50 mg) for the prevention of PONV in 635 females undergoing outpatient laparoscopic gynecologic surgery. Antiemetic efficacy was evaluated over a 24-h postoperative period by recording the number and timing of emetic episodes; effects on nausea were evaluated by a visual analog scale (VAS). The proportion of complete responders (no emetic episodes and no escape medication in 24 h) was significantly higher with each dolasetron mesylate dose (> 50% for each dose; P < or = 0.0003) than with placebo (30.6%). Fewer patients given dolasetron required or requested escape antiemetic medication compared with placebo (P < 0.0003). Dolasetron-treated patients had significantly (P < 0.0357) lower median postdose maximum nausea VAS scores compared with placebo-treated patients. Patient satisfaction with dolasetron was high and, overall, was significantly (P = 0.0131) greater than that with placebo. Dolasetron was an effective and well tolerated preventive treatment for PONV resulting from laparoscopic gynecologic surgery.

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 (i.v.) dolasetron dosing regimens in patients receiving their first course of high-dose (> or = 80 mg/m2) cisplatin. Of 30 patients enrolled, 14 received a single i.v. dolasetron dose (0.6 mg/kg) before cisplatin and 16 received a multiple i.v. 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 had 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.

Oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy. Oral Dolasetron Dose Response Study Group.

PURPOSE: This double-blind, dose-response study was conducted to assess the safety and efficacy of four oral doses of dolasetron mesylate for preventing acute emesis in cancer patients receiving their first course of moderately emetogenic platinum-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive a single oral dose of 25, 50, 100, or 200 mg dolasetron 30 minutes before receiving IV carboplatin (275-400 mg/m2)- or cisplatin (20-50 mg/m2)-containing chemotherapy, then monitored for nausea and vomiting for 24 hours. RESULTS: Three hundred seven cancer patients from 32 sites completed the study. There was a statistically significant dose response across the four doses for complete response (no emetic episodes or rescue medication): 44.7%, 71.3%, 73.2%, and 82.5% for the 25, 50, 100, or 200 mg doses of dolasetron, respectively. Patients' nausea severity and patient satisfaction visual analogue scale scores also showed a statistically significant trend with dose. All doses of dolasetron were well tolerated. The most common adverse events were headache (17.6%) and dizziness (2.0%). DISCUSSION: This study demonstrates the safety and antiemetic efficacy of oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy with the highest antiemetic activity observed at 200 mg.

Pharmacokinetics of dolasetron after oral and intravenous administration of dolasetron mesylate in healthy volunteers and patients with hepatic dysfunction.

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.

Antiemetic efficacy of two different single intravenous doses of dolasetron in patients receiving high-dose cisplatin-containing chemotherapy.

This randomized, double-blind, parallel-group, multicenter study compared the antiemetic effectiveness, safety, and tolerability of two different intravenous (i.v.) doses of dolasetron mesylate (0.6 and 1.8 mg/kg) in cancer patients receiving their first course of high-dose cisplatin-containing chemotherapy (> or = 75 mg/m2). Efficacy was assessed by recording the timing, number, and severity of emetic episodes in the 24 h following high-dose cisplatin. Safety was evaluated by monitoring adverse events, vital signs, clinical laboratory parameters, and electrocardiograms. Of the 62 patients enrolled in the study, 29 received 0.6 mg/kg of dolasetron mesylate and 33 received 1.8 mg/kg. Patients who received dolasetron mesylate 1.8 mg/kg consistently experienced a greater degree of antiemetic control than those who received 0.6 mg/kg. Complete responses were achieved by 55% of patients who received 1.8 mg/kg compared with 31% for the 0.6-mg/kg group. The 1.8-mg/kg group achieved a significantly (p = 0.039) higher complete/ major response rate than the 0.6-mg/kg group (77% vs 55%, respectively) and a significantly (p = 0.004) longer time to the first emetic episode (> 24 h vs 13.5 h, respectively). More than 80% of patients were either satisfied or very satisfied with dolasetron treatment. The most common adverse events were mild to moderate in intensity, consistent with other studies, and included headache (24.1% of patients) and diarrhea (4.8%). These results demonstrated that a single 1.8-mg/kg i.v. dose of dolasetron mesylate provided effective antiemetic activity in a majority of patients given high-dose cisplatin for the first time and should be evaluated further in clinical 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.

Single-dose, placebo-controlled, phase I study of oral dolasetron.

STUDY OBJECTIVES: To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5-HT3 receptor antagonist. DESIGN: Double-blind, placebo-controlled, dose-escalating phase I study. SETTING: A clinical research center. PATIENTS: One hundred twenty healthy male volunteers. INTERVENTIONS: Subjects received either placebo or oral dolasetron mesylate 50, 100, 150, 200, 250, 300, or 400 mg. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, subjects receiving dolasetron mesylate reported a greater frequency of headache, light-headedness, dizziness, increased appetite, and nausea. There were no clinically significant changes in mean laboratory values from before to after treatment. Adverse events were transient, mild or moderate, and similar to those after single intravenous doses of the drug. No clinically significant electrocardiographic changes occurred, but lengthening of the QRS complex duration and dose-dependent lengthening of PR and QTc intervals were observed 1-2 hours after dosing. These effects were asymptomatic and were mainly associated with higher doses (< or = 300 mg). CONCLUSION: Dolasetron mesylate is well tolerated when administered in single oral doses up to 400 mg to healthy volunteers. Clinical trials are under way to evaluate the agent's efficacy in preventing chemotherapy-induced and postoperative nausea and vomiting with doses up to 200 mg.

Multiple-dose, placebo-controlled, phase I study of oral dolasetron.

STUDY OBJECTIVES: To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5-HT3 antagonist. DESIGN: Double-blind, placebo-controlled, dose-ranging phase I study. SETTING: A clinical research center. PATIENTS: Forty healthy male volunteers. INTERVENTIONS: Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2-8, or placebo for 9 days. MEASUREMENTS AND MAIN RESULTS: Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron- and placebo-treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose-response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment-related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple-dose exposure of this metabolite can be predicted from its single-dose values. CONCLUSION: Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.

A randomized, double-blind comparison of single-dose and divided multiple-dose dolasetron for cisplatin-induced emesis.

PURPOSE: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. METHODS: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin ( > or = 80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. RESULTS: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P = 0.034) longer median time to the first emetic episode (10.1 h vs > 24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. CONCLUSIONS: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration.