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.

Pharmacokinetics of dolasetron with coadministration of cimetidine or rifampin in healthy subjects.

PURPOSE: Dolasetron is a selective 5-HT3 receptor antagonist. The purpose of this study was to determine the effect of cimetidine and rifampin on the steady-state pharmacokinetics of orally administered dolasetron and its active reduced metabolite, hydrodolasetron. METHODS: A group of 18 healthy men (22 to 44 years old) were randomized to receive each of the following three treatments in a three-period cross-over design: 200 mg dolasetron daily (treatment A); 200 mg dolasetron daily plus 300 mg cimetidine four times daily (treatment B); or 200 mg dolasetron daily plus 600 mg rifampin daily (treatment C). Each study period was separated by a 14-day washout period. Serial blood samples were collected before the first dose (baseline) on day 1 and at frequent intervals up to 48 h after the morning dose on day 7 for quantification of dolasetron and its metabolites, hydrodolasetron (both isomers), 5'OH hydrodolasetron, and 6'OH hydrodolasetron. Serial urine samples were also collected at baseline and during the periods 0-24 and 24-48 h following the morning dose on day 7, and analyzed for dolasetron and its metabolites. RESULTS: Plasma and urine dolasetron concentrations were below quantifiable concentrations for all three treatments. Mean steady-state area under the plasma concentration-time curve (AUCss(0-24)) of hydrodolasetron increased by 24%, mean apparent clearance (CLapp.po) decreased by 19%, and maximum plasma hydrodolasetron concentration (Cmax,ss) increased by 15% when dolasetron was coadministered with cimetidine. When dolasetron was given with rifampin, mean hydrodolasetron AUCss(0-24) decreased by 28%, CLapp.po, increased by 39%, and hydrodolasetron Cmax,ss decreased by 17%. Small differences were found in mean tmax (0.7 to 0.8 h), CLr (2.0 to 2.6 ml/min per kg), and t1/2 (7.4 to 8.8 h) for hydrodolasetron between treatment periods. Approximately 20% and 2% of the dolasetron dose were excreted in urine as the R(+) isomer and S(-) isomer of hydrodolasetron, respectively, across all three treatments. Dolasetron mesylate was well tolerated in this study during all three treatment periods, with the highest incidence of adverse events reported during the control period when dolasetron mesylate was given alone. CONCLUSION: Based on the small changes in the pharmacokinetic parameters of dolasetron and its active metabolites, as well as the favorable safety results, no dosage adjustments for dolasetron mesylate are recommended with concomitant administration of cimetidine or rifampin.

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).

Pharmacokinetics of oral and intravenous dolasetron mesylate in patients with renal impairment.

In an open-label, randomized, two-way complete crossover study, the influence of renal impairment on the pharmacokinetics of dolasetron and its primary active metabolite, hydrodolasetron, were evaluated. Patients with renal impairment were stratified into three groups of 12 based on their 24-hour creatinine clearance (Cl(cr)): group 1, mild impairment (Cl(cr) between 41 and 80 mL/min); group 2, moderate impairment (Cl(cr) between 11 and 40 mL/min); and group 3, endstage renal impairment (Cl(cr) < or = 10 mL/min). Twenty-four healthy volunteers from a previous study served as the control group. Each participant received a single intravenous or oral 200-mg dose of dolasetron mesylate on separate occasions. Serial blood samples were collected up to 60 hours after dose for determination of dolasetron and hydrodolasetron, and urine samples were collected in intervals up to 72 hours for determination of dolasetron, hydrodolasetron, and the 5' and 6'-hydroxy metabolites of hydrodolasetron. Because plasma concentrations were low and sporadic, pharmacokinetic parameters of dolasetron were not calculated after oral administration. Although some significant differences in area under the concentration-time curve (AUC0-infinity), volume of distribution (Vd), systemic clearance (Cl), and elimination half-life (t1/2) of the parent drug were observed between control subjects and patients with renal impairment, there were no systematic findings related to degree of renal dysfunction. The elimination pathways of hydrodolasetron include both hepatic metabolism and renal excretion. Consistent increases in mean Cmax, AUC0-infinity, and t1/2 and decreases in renal and total apparent clearance of hydrodolasetron were seen with diminishing renal function after intravenous administration of dolasetron mesylate. No consistent changes were found after oral administration. Urinary excretion of hydrodolasetron and its metabolites decreased with decreasing renal function, but the profile of metabolites remained constant. Dolasetron was well tolerated in all three groups of patients. Based on these findings, no dosage adjustment for dolasetron is recommended in patients with renal impairment.

Effect of infusion rate on the pharmacokinetics and tolerance of intravenous dolasetron mesylate.

OBJECTIVE: To evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dolasetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group study. METHODS: Forty-nine healthy nonsmoking male volunteers were randomly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo. Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/min). Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study drug. Serial blood samples and 12-lead electrocardiogram measurements were obtained for 24 hours after the infusion. Plasma samples were analyzed for dolasetron and hydrodolasetron. RESULTS: Dolasetron mesylate was well tolerated, with no apparent differences in vital signs or adverse event profiles among the different rates of infusion. In general, the pharmacokinetics of dolasetron and hydrodolasetron were superimposable among the three infusion rate groups. Plasma dolasetron concentrations declined rapidly in all three infusion rate groups, with mean elimination half-life (t1/2) of less than 10 minutes. The reduced metabolite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t1/2 of 8-9 hours. The correlation coefficients of least-squares regression analysis between the pharmacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, suggesting that none of the hydrodolasetron pharmacokinetic parameters were affected by rate of infusion. CONCLUSIONS: The intravenous administration of dolasetron 100 mg over 0.5-2 minutes did not significantly alter the pharmacokinetic profiles of either dolasetron or hydrodolasetron. In addition, the safety profile of dolasetron did not change with increasing rate of infusion. Therefore, the rate of infusion of dolasetron mesylate appears to have no pharmacokinetic or clinical implications when assessed over a 0.5-2-minute time period.

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.

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.

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.

beta-Adrenergic blocking agents. alpha- and gamma-methyl(aryloxy)propanolamines.

A series of gamma-methyl- (5) and alpha-methyl(aryloxy)propanolamines (6) were synthesized and evaluated for beta-adrenergic blocking action. The binding constant (KD) was determined for compounds 5a-j on cultured C6-2B astrocytoma cells. Compounds 5a-j and 6a-e were evaluated for beta 1-antagonist action on guinea pig atria and beta 2-antagonist action on guinea pig tracheal strips. Several gamma-methyl(aryloxy)propanolamines showed affinity for beta receptors and a possible preference for beta 2 receptors.

Heterocyclic tricycles as potential CNS agents I: 4-aminoalkylindeno[1,2-c]pyrazoles.

Series of 4-(3-dimethylaminopropyl)-4-hydroxyindeno[1,2-c]pyrazoles and 4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c-]pyrazoles were synthesized and identified. The compounds were evaluated as potential CNS agents using spontaneous and forced motor activity in mice as an initial test. 2-Ethyl-3-methyl-4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c]pyrazole possessed significant biological activity.

Rectal absorption of homatropine [14C]methylbromide in the rat.

Homatropine[14C]methylbromide (HMB-14C) was administered to rats by intramuscular injection, oral gavage and rectal suppository. Plasma concentration of 14C were measured over the subsequent 12 h. Peak plasma concentrations were higher and achieved more rapidly after rectal administration than by the other routes whether HMB-14C was administered in a water-soluble suppository base or in aqueous solution. Twelve h after the suppositories were inserted and retained 28% of the 14C had been excreted in the urine while 56% remained in the large intestine. Unlabelled HMB, given in rectal suppositories to anaesthetized rats, caused prompt blockade of the effects of vagal stimulation on pulse rate and of intravenous acetylcholine on blood pressure. These results confirm the rapid rectal absorption of the drug.

Phosphorus-nitrogen compounds. 21. Murine oncolytic and antifertility effect of adamantylaziridine compounds.

P,P-Bis(1-aziridinyl)-N-adamantylphosphinic amide and N,N'-bis(ethylene)-P-(1-adamantyl)phosphonic diamide were synthesized as potential anticancer and male antifertility agents. Log P values (octanol-water) of the agents were determined and compared to calculated values. Both derivatives displayed intraperitoneal murine antileukemic activity and antifertility effects when given intraperitoneally and orally.

Phosphorus-nitrogen compounds XIX: distribution of 32P and effect of an active oncolytic on intracerebral leukemia in rodents.

P,P-Bis(1-aziridinyl)-N-1-adamantylphosphinic amide displayed oncolytic activity against intracerebral and intraperitoneal L-1210 leukemia. Administration of the isotope-labeled compound to rats shows 32P distribution to the brain.

Synthesis and biological actions of 2-substituted quinolizidines.

A series of 2-substituted quinolizidines was synthesized and tested for their effects on motor activity in mice. In the 2-aryl-2-hydroxyquinolizidines (5 and 6) a difference was noted in potency between the axial and equatorial aryl analogs. A significant difference in activity was also found between the epimeric 2-(4-fluorobenzoyl) quinolizidines (10c and 11c).