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

Dimmitt, Dan C.; Choo, Youn Sung; Martin, Lorene A.; Arumugham, Thangam; Hahne, William F.; Weir, Scott J.

doi:10.1002/(sici)1099-081x(199901)20:1<29::aid-bdd151>3.0.co;2-s

Cited by 15 publications

(5 citation statements)

References 16 publications

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“…Using this method, the bioavailability of dolasetron is approximately 76%. 1 Coadministration of dolasetron with food delays the time to maximum plasma concentration, but the overall extent of absorption is not significantly affected. 5 Results of additional dolasetron pharmacokinetic studies have demonstrated no clinically significant drug accumulation with multiple doses administered daily over 5 days.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…However, these pharmacokinetic advantages do not appear to translate into meaningful clinical benefit (i.e., improved efficacy or safety ) in treating chemotherapy-induced emesis. 1 …”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…Thus, the R ( + ) enantiomer of hydrodolasetron is believed to be chiefly responsible for the antiemetic activity observed with dolasetron. 1,2 Because the parent drug is only detected in plasma for less than 1 hour after a single 100 -mg oral dose, hydrodolasetron is measured to assess its pharmacokinetic profile.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…Following iv administration, dolasetron (50 ± 200 mg ) disappears rapidly from the blood stream, with a half -life of approximately 10 minutes. In contrast, dolasetron is rarely detected in the blood stream after oral administration of 200 mg. 1,2 The pharmacokinetics of dolasetron are linear over a dose range of 50 to 200 mg. There is a dose -dependent increase in the area under the curve ( AUC ) , but half -life, clearance, and volume of distribution are constant.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

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A review of dolasetron as management of nausea and vomiting in cancer patients

Valley

2000

J Oncol Pharm Pract

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Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…However, these pharmacokinetic advantages do not appear to translate into meaningful clinical benefit (i.e., improved efficacy or safety ) in treating chemotherapy-induced emesis. 1 …”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

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A review of dolasetron as management of nausea and vomiting in cancer patients

Valley

2000

J Oncol Pharm Pract

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“…For reprints contact: Reprints@AlphaMedPress.com dolasetron with 24 healthy males, one participant was identified as a CYP2D6 poor metabolizer, having a urinary metabolite level that differed markedly from the other participants [9]. Theoretically, he was at high risk for a potential drugdrug interaction due to prolonged concentrations of the active metabolite of dolasetron in his body.…”

mentioning

confidence: 99%

In Reply: Evidence for Equivalent Cardiotoxicity of the 5-HT3 Receptor Antagonists

Goodin

Cunningham

2003

The Oncologist

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The response by Dr. Ellis and Dr. Dozier to our article and that of Dr. Keefe's, which recently appeared in The Oncologist [1][2][3], suggests that the available antiemetics in this classgranisetron, ondansetron, and dolasetron-share a similar cardiovascular side-effect profile. Although their conclusions are worthy of consideration, I would like to also highlight additional information.It is suggested that alterations in electrocardiographic (ECG) intervals are a class effect. While it was acknowledged in our original manuscript [1] that the class of 5-HT 3 receptor antagonists has been reported to produce small, statistically significant, but clinically asymptomatic, changes in ECG parameters, the susceptibility for inducing cardiac effects varies among these agents. Additionally, in discussing the cardiovascular effects, we focused our paper on QTc prolongation, and not ECG changes in general. We do not dispute that the data for dolasetron are comprehensive nor that the frequency of small transient ECG changes with dolasetron is comparable with other 5-HT 3 receptor antagonists; however, it is the magnitude of these changes with escalating doses or increased plasma concentrations, secondary to potential drug-drug interactions, of dolasetron that give cause for concern. We agree that after 24 hours following administration of 5-HT 3 receptor antagonists, equivalent alterations in cardiac conduction intervals have been demonstrated, suggesting a class effect. However, during the first 1-2 hours after drug administration, dolasetron has been shown to produce greater changes in these parameters than either granisetron [4] or ondansetron [5]. Specifically, patients receiving dolasetron, 1.8 and 2.4 mg/kg i.v., had significantly greater (p = 0.0016) increases in QTc interval than patients administered granisetron at the high European dose (3 mg i.v.) [4]. As stated in our original review, there is a known validated link between QTc elongation and cardiovascular risk in the form of torsades de pointes, which can sometimes prove fatal. We agree the risk is likely minimal following dolasetron monotherapy in healthy patients; however, in reality, patients receive their 5-HT 3 receptor antagonists as part of a polypharmacy regimen. It is in this patient population that we recommend caution be taken regarding the risk of drug interactions for all medications, including the 5-HT 3 receptor antagonists. Of additional concern is that cancer is a disease of the elderly, and it has been documented that the majority of elderly cancer patients with comorbid conditions are receiving multiple medications [6,7]. Many of these medications possess cardiovascular warnings. Therefore, consideration must be given to the possibility of in vivo drug-drug interactions in individual patients and the risk from concomitant medications that may produce additive QTc interval prolongations.The metabolism of the 5-HT 3 receptor antagonists is an area we feel has been overlooked by many in contributing to the toxicities of this class of drugs, in...

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