Dolasetron mesylate and its active metabolite, hydrodolasetron (MDL 74,156), are selective serotonin 5-HT3 receptor antagonists not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. The serotonin 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that the released serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the vomiting reflex.
Acute, usually reversible, ECG changes (PR and QTc prolongation; QRS widening), caused by dolasetron mesylate, have been observed in healthy volunteers and in controlled clinical trials. The active metabolites of dolasetron may block sodium channels, a property unrelated to its ability to block 5-HT3 receptors. QTc prolongation is primarily due to QRS widening. Dolasetron appears to prolong both depolarization and, to a lesser extent, repolarization time. The magnitude and frequency of the ECG changes increased with dose (related to peak plasma concentrations of hydrodolasetron but not the parent compound). These ECG interval prolongations usually returned to baseline within 6 to 8 hours, but in some patients were present at 24 hour follow up. Dolasetron mesylate administration has little or no effect on blood pressure.
In healthy volunteers (N=64), dolasetron mesylate in single intravenous doses up to 5 mg/kg produced no effect on pupil size or meaningful changes in EEG tracings. Results from neuropsychiatric tests revealed that dolasetron mesylate did not alter mood or concentration. Multiple daily doses of dolasetron have had no effect on colonic transit in humans. Dolasetron has no effect on plasma prolactin concentrations.
Pharmacokinetics in Humans
Oral dolasetron is well absorbed, although parent drug is rarely detected in plasma due to rapid and complete metabolism to the most clinically relevant species, hydrodolasetron.
The reduction of dolasetron to hydrodolasetron is mediated by a ubiquitous enzyme, carbonyl reductase. Cytochrome P-450 (CYP)IID6 is primarily responsible for the subsequent hydroxylation of hydrodolasetron and both CYPIIIA and flavin monooxygenase are responsible for the N-oxidation of hydrodolasetron.
Hydrodolasetron is excreted in the urine unchanged (61.0% of administered oral dose). Other urinary metabolites include hydroxylated glucuronides and N-oxide.
Hydrodolasetron appears rapidly in plasma, with a maximum concentration occurring approximately 1 hour after dosing, and is eliminated with a mean half-life of 8.1 hours (%CV=18%) and an apparent clearance of 13.4 mL/min/kg (%CV=29%) in 30 adults. The apparent absolute bioavailability of oral dolasetron, determined by the major active metabolite hydrodolasetron, is approximately 75%. Orally administered dolasetron intravenous solution and tablets are bioequivalent. Food does not affect the bioavailability of dolasetron taken by mouth.
Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly, glucuronidation and hydroxylation. Two thirds of the administered dose is recovered in the urine and one third in the feces. Hydrodolasetron is widely distributed in the body with a mean apparent volume of distribution of 5.8 L/kg (%CV=25%, N=24) in adults.
Sixty-nine to 77% of hydrodolasetron is bound to plasma protein. In a study with 14C labeled dolasetron, the distribution of radioactivity to blood cells was not extensive. Approximately 50% of hydrodolasetron is bound to α1-acid glycoprotein. The pharmacokinetics of hydrodolasetron are linear and similar in men and women.
The pharmacokinetics of hydrodolasetron, in special and targeted patient populations following oral administration of dolasetron, are summarized in Table 1. The pharmacokinetics of hydrodolasetron are similar in adult (young and elderly) healthy volunteers and in adult cancer patients receiving chemotherapeutic agents. The apparent clearance following oral administration of hydrodolasetron is approximately 1.6- to 3.4-fold higher in children and adolescents than in adults. The clearance following oral administration of hydrodolasetron is not affected by age in adult cancer patients. The apparent oral clearance of hydrodolasetron decreases 42% with severe hepatic impairment and 44% with severe renal impairment. No dose adjustment is necessary for elderly patients (see PRECAUTIONS, Geriatric Use) or for patients with hepatic or renal impairment.
The pharmacokinetics of ANZEMET Tablets have not been studied in the pediatric population. However, the following pharmacokinetic data are available on intravenous ANZEMET Injection administered orally to children.
Thirty-two pediatric cancer patients ages 3 to 11 years (N=19) and 12 to 17 years (N=13), received 0.6, 1.2, or 1.8 mg/kg ANZEMET Injection diluted with either apple or apple-grape juice and administered orally. In this study, the mean apparent clearances of hydrodolasetron were 3 times greater in the younger pediatric group and 1.8 times greater in the older pediatric group than those observed in healthy adult volunteers. Across this spectrum of pediatric patients, maximum plasma concentrations were 0.6 to 0.7 times those observed in healthy adults receiving similar doses.
For 12 pediatric patients, ages 2 to 12 years receiving 1.2 mg/kg ANZEMET Injection diluted in apple or apple-grape juice and administered orally, the mean apparent clearance was 34% greater and half-life was 21% shorter than in healthy adults receiving the same dose.
Table 1. Pharmacokinetic Values for Plasma Hydrodolasetron Following Oral Administration of ANZEMETmean values
|CLapp: apparent clearance t1/2: terminal elimination half-life (): coefficient of variation in %|
|Young Healthy Volunteers (N=30)||19–45||200 mg||13.4 (29%)||8.1 (18%)||556 (28%)|
|Elderly Healthy Volunteers (N=15)||65–75||2.4 mg/kg||9.5 (36%)||7.2 (32%)||662 (28%)|
| Adults (N=61)analyzed by nonlinear mixed effect modeling with data pooled across dose strengths||24–84||25–200 mg||12.9 (49%)||7.9 (43%)||--sampling times did not allow calculation|
| Adolescents (N=13)||12–17||0.6–1.8 mg/kg||26.5 (67%)||6.4 (30%)||374results from adolescents (dose=1.8 mg/kg, N=3)(32%)|
| Children (N=19)||3–11||0.6–1.8 mg/kg||44.2 (49%)||5.5 (39%)||217results from children (dose=1.8 mg/kg, N=7)(67%)|
|Pediatric Surgery Patients (N=11)||2–12||1.2 mg/kg||20.8 (49%)||5.9 (24%)||159 (32%)|
|Patients with Severe Renal|
(Creatinine clearance ≤10 mL/min)
|28–74||200 mg||7.2 (48%)||10.7 (29%)||701 (21%)|
|Patients with Severe Hepatic|
|42–52||150 mg||8.8 (57%)||11.0 (36%)||410 (12%)|
Prevention of Cancer Chemotherapy-Induced Nausea and Vomiting
Oral ANZEMET at a dose of 100 mg prevents nausea and vomiting associated with moderately emetogenic cancer therapy as shown by 24 hour efficacy data from two double-blind studies. Efficacy was based on complete response (ie, no vomiting, no rescue medication).
The first randomized, double-blind trial compared single oral ANZEMET doses of 25, 50, 100 and 200 mg in 60 men and 259 women cancer patients receiving cyclophosphamide and/or doxorubicin. There was no statistically significant difference in complete response between the 100 mg and 200 mg dose. Results are summarized in Table 2.
Table 2. Prevention of Chemotherapy-Induced Nausea and Vomiting from Moderately Emetogenic Chemotherapy
|Response Over 24 Hours||ANZEMET Tablets|
|100 mgThe recommended dose|
| p -value|
|Complete ResponseNo emetic episodes and no rescue medication.||24 (31%)||34 (41%)|| 49 (61%) ||46 (59%)||P<.0001|
|Nausea ScoreMedian 24-h change from baseline nausea score using visual analog scale (VAS): Score range 0="none" to 100="nausea as bad as it could be."||49||10|| 11 ||7||P=.0006|
Another trial also compared single oral ANZEMET doses of 25, 50, 100, and 200 mg in 307 patients receiving moderately emetogenic chemotherapy. In this study, the 100 mg ANZEMET dose gave a 73% complete response rate.
Prevention of Postoperative Nausea and Vomiting
ANZEMET Tablets at a dose of 100 mg administered orally 1-2 hours before surgery and before general balanced anesthesia (short-acting barbiturate, nitrous oxide, narcotic analgesic, and skeletal muscle relaxant) was significantly more effective than placebo in preventing postoperative nausea and vomiting. Efficacy was based on complete response rates (0 emetic episodes and no rescue medication over 24 hours). No increased efficacy was seen with higher doses.
One trial compared single ANZEMET Tablet doses of 25, 50, 100, and 200 mg with placebo in 789 women undergoing gynecological surgery. In this study the 100 mg dose produced a complete response rate statistically superior to placebo. The study results are summarized in Table 3.
Table 3. Prevention of Postoperative Nausea and Vomiting
|Response Over 24 Hours||ANZEMET Tablets|
|100 mgThe recommended dose|
|Complete ResponseNo emetic episodes and no rescue medication.||71 (45%)||95 (57%)
|| 78 (51%) ||73 (47%)||55 (35%)|
|Nausea ScoreMedian 24-h change from baseline nausea score using visual analog scale (VAS): Score range 0="none" to 100="nausea as bad as it could be."||5||4|| 5 ||6||15|
Another trial also compared single oral ANZEMET doses of 25, 50, 100, and 200 mg with placebo in 373 women undergoing gynecological surgery. In this study, the 100 mg ANZEMET dose gave a 54% complete response rate as compared to the 29% rate of placebo.