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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.
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.
Effects on Electrocardiogram
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 80 healthy adults, with 14 measurements over 24 hours on Day 4. The maximum mean (95% upper confidence bound) differences in QTcF from placebo after baseline-correction were 14.1 (16.1) and 36.6 (38.6) ms for 100 mg and supratherapeutic 300 mg ANZEMET, administered intravenously, respectively. ANZEMET 300 mg once daily resulted in approximately 3-fold higher mean Cmax values of dolasetron mesylate and its active metabolite hydrodolasetron on Day 4 compared to those observed with the therapeutic 100 mg ANZEMET dose.
Based on exposure-response analysis in healthy volunteers, QTc interval prolongations appear to be associated with concentrations of hydrodolasetron. Using the established exposure-response relationship, the mean predicted increase (95% upper prediction interval) in QTcF intervals were 16.0 (17.1) and 17.9 (19.1) ms for renally impaired and elderly subjects following an oral dose of 100 mg.
In the thorough QT study, exposure dependent prolongation of the PR and QRS interval was also noted in healthy subjects receiving ANZEMET. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.8 (11.6) ms and 33.1 (34.9) ms for 100 mg and supratherapeutic 300 mg ANZEMET, respectively. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 3.5 (4.5) ms and 13 (14.5) ms for 100 mg and supratherapeutic 300 mg ANZEMET, respectively. Over one-fourth of the subjects treated with the 300 mg dose had an absolute PR over 200 ms and absolute QRS of over 110 ms post-treatment. A change from baseline ≥ 25% was noted in several of these subjects. (see WARNINGS)
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)2D6 is primarily responsible for the subsequent hydroxylation of hydrodolasetron and both CYP3A 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 renally impaired or elderly patients, however ECG monitoring is recommended (see WARNINGS and PRECAUTIONS, Geriatric Use). No dose adjustment is recommended for patients with hepatic 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.
The table below summarizes the pharmacokinetic data from multiple populations. Please note that the doses studied may have exceeded the maximum recommended dose.
Table 1: Pharmacokinetic Values for Plasma
Hydrodolasetron Following Oral Administration of ANZEMET*
|Age (years)||Dose||CLapp (mL/min/kg)||t½ (h)||Cmax (ng/mL)|
|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)†||24-84||25-200 mg||12.9 (49%)||7.9 (43%)||--‡|
|Adolescents (N=13)||12-17||0.6-1.8 mg/kg||26.5 (67%)||6.4 (30%)||374§ (32%)|
|Children (N=19)||3-11||0.6-1.8 mg/kg||44.2 (49%)||5.5 (39%)||217|| (67%)|
|Patients with Severe Renal Impairment (N=12) (Creatinine clearance ≤ 10 mL/min)||28-74||200 mg||7.2 (48%)||10.7 (29%)||701 (21%)|
|Patients with Severe Hepatic Impairment (N=3)||42-52||150 mg||8.8 (57%)||11.0 (36%)||410 (12%)|
|CLapp: apparent clearance t½: terminal elimination
half-life ( ): coefficient of variation in %
*: mean values
†: analyzed by nonlinear mixed effect modeling with data pooled across dose strengths
‡: sampling times did not allow calculation
§: results from adolescents (dose=1.8 mg/kg, N=3) the maximum dose exceeded 100 mg. When data from patients who received greater than 47 mg (N=9) are combined and normalized to the 1.8 mg/kg dose with a cap of 100 mg, the mean Cmax was 229 ng/mL (51%).
| |: results from children (dose=1.8 mg/kg, N=7)
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 (i.e., 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|
|p-value for Linear Trend|
|Complete Response‡||24 (31%)||34 (41%)||49 (61%)||46 (59%)||P < 0001|
|†: The recommended dose
‡: No emetic episodes and no rescue medication.
§: Median 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.”
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.
Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.
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