Open-Label Comparison of the Antiemetic Efficacy of Single Intravenous Dosesof Dolasetron Mesylate in Pediatric Cancer Patients Receiving Moderately to

Highly Emetogenic Chemotherapy

Max J. Coppes, MD, PhD,1* Robert Lau, MD,2 Lewis C. Ingram, PhD,3

John T. Wiernikowski, PharmD,4 Ronald Grant, MD,1 Danny R. Howard, PhD,5

Maria Perrotta, BA,6 Ronald Barr, MB, ChB, MD,4 Ellen Dempsey, MSc,6

Mark L. Greenberg, MD,2 and Jean-Marie Leclerc, MD7

Background. Nausea and vomiting areamong the most unpleasant adverse side effectsof cancer therapy. Procedure. An open-labeldose-escalation study was conducted to assessthe appropriate intravenous dose of dolasetronfor pediatric patients undergoing chemo-therapy. Patients received dolasetron in singleintravenous doses of 0.6 (n = 10), 1.2 (n = 12),1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 minbefore receiving emetogenic chemotherapy.Pharmacokinetic parameters were evaluated ateach dose level and efficacy was evaluatedover the first 24 hr following the administrationof dolasetron. Results. A complete responsewas achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1.2 mg/kg, 67% ofpatients given 1.8 mg/kg, and 33% of patients

given 2.4 mg/kg. Peak plasma concentrations(Cmax) were observed between 0.33 and 0.75 hrfollowing dolasetron infusion. Cmax and areaunder plasma concentration-time (AUC) in-creased with larger doses of dolasetron, whileterminal disposition half-life (t1/2) and appar-ent clearance (Clapp) were not significantlychanged with respect to dose. For 1.8-mg/kgdolasetron, the t1/2 was 4.98 hr and the maxi-mum plasma concentration (tmax) 0.47 hr. Ad-verse events were mild to moderate. No seriousevents occurred. Conclusions. This study sug-gests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose forcontrolling chemotherapy-induced emesis inpediatric patients. Med. Pediatr. Oncol. 33:99–105, 1999. © 1999 Wiley-Liss, Inc.

Key words: 5-HT3 antagonist; antiemetic; dolasetron; chemotherapy; cancer;children; nausea; vomiting

INTRODUCTION

Phenothiazines, butyrophenones, antihistamines, cor-ticosteroids, and cannabinoids all confer antiemetic prop-erties and as such have been and still are used alone or incombination in the prevention and management of che-motherapy-induced nausea and vomiting [1,2]. Until re-cently, the dopamine receptor antagonist metoclopramidewas considered the cornerstone of antiemetic treatment.It confers antiemetic protection at high doses [3] but isassociated with extrapyramidal side effects, especially inchildren, adolescents, and young adults [4–6].

In the last decade there has been much interest in therole of serotonin in the emetic process. Clinically, sero-tonin has been implicated in a number of disorders asreflected in the presence of several receptors that mediateits effects. One of these, the type 3 receptor (5-HT3 re-ceptor) has turned out to have a pivotal role in the processof emesis. 5-HT3 receptors are abundant on vagal affer-ent neurons and other neurons in the gastrointestinal tractand have also been identified in the area postrema, in thenucleus tractus solitarii, and presynaptcally on vagal af-ferent terminals in the medulla [7]. And indeed, the in-

troduction of 5-HT3 receptor antagonists has revolution-ized the management of nausea and vomiting [8]. Cur-rently, several 5-HT3 receptor antagonists are availablefor clinical use. These include ondansetron, granisetron,

1Alberta Children’s Hospital and Tom Baker Cancer Centre, Calgary,Alberta, Canada2Hospital for Sick Children, Toronto, Ontario, Canada3Janeway Child Health Centre, St John’s, Newfoundland, Canada4McMaster University, Hamilton, Ontario, Canada5U.S. Clinical Pharmacokinetics, Hoechst Marion Roussel Inc., Kan-sas City, Missouri6Departments of Clinical Research and Statistics Hoechst MarionRoussel Canada Research Inc., Laval, Quebec, Canada7Hopital Sainte-Justine, Montre´al, Quebec, Canada

Max J. Coppes is a clinical investigator of the Alberta Heritage Foun-dation for Medical Research (AHFMR).

*Correspondence to: Dr. Max J. Coppes, Southern Alberta Children’sCancer Program, Alberta Children’s Hospital, 1820 Richmond RoadSW, Calgary, Alberta, T2T 5C7, Canada.E-mail: max.coppes@crha-health.ab.ca

Received 22 May 1998; Accepted 9 February 1999

Medical and Pediatric Oncology 33:99–105 (1999)

© 1999 Wiley-Liss, Inc.

and tropisetron. In the pediatric setting, it is not clearwhether one of the 5-HT3 receptor antagonists is superiorto the other two, nor whether one provides antiemeticefficacy in situations where the other 5-HT3 receptorantagonists are not effective.

Dolasetron mesylate (Anzemet, MDL 73,147EF,Hoechst Marion Roussel) is a new and highly selective5-HT3 antagonist [9–11] that is rapidly reduced to MDL74,156, a metabolite with greater activity and a longerhalf-life than the parent compound [9,12]. In adults, ter-minal disposition half-life (t1/2) is approximately 7.5 hrwith an apparent clearance of 9.3 to 9.5 ml/min/kg(Hoechst Marion Roussel Canada Research). Dolasetronhas been shown to be effective and well tolerated inrandomized, double-blind trials in adult patients under-going high-dose cisplatin chemotherapy [13–15]. How-ever, conclusions drawn from clinical studies in adultscannot necessarily be extrapolated to children [16,17].Preliminary data for example, suggest that the apparenttotal plasma clearance of MDL 74,156, the major activemetabolite of dolasetron, is greater in children than inadults [18], resulting in a smaller t1/2. Thus, trials of newtherapies in pediatric populations remain essential.

We conducted an open-label, nonrandomized dose-escalation study in children to determine the single in-travenous dose of dolasetron that would be appropriatefor further study in pediatric cancer patients receivingmoderately to highly emetogenic chemotherapy [19].Plasma pharmacokinetics for MDL 74,156, the majoractive metabolite of dolasetron, were also evaluated.

MATERIALS AND METHODSPatients

Chemotherapy-naive and non-naive patients, betweenthe ages of 3 and 18 years, inclusive, and weighing atleast 18 kg were eligible for the study. All patients hadhistologically confirmed malignant disease, a Karnofskyperformance status of$50%, and scheduled to receivemoderately to highly emetogenic chemotherapy (TableI). Written informed consent was obtained for all pa-tients; when appropriate, assent was sought from partici-pants.

Excluded from the study were those having receivedany drug known to have potential antiemetic efficacy orsedating properties within 24 hr of study drug adminis-tration; general anesthetic agents within 72 hr of studyday; or any investigational drug within 30 days or 5 timesits half-life, whichever was longest, before study day.Female adolescents who had a positive pregnancy testwere ineligible for the trial. Also excluded were thosewith a history of hypersensitivity to 5-HT3 antagonists;vomited from any etiology of Southwest OncologyGroup grade 2 or 3 within the 24 hr preceding chemo-therapy; evidence of liver disease (AST/ALT) > 3 times

the upper limit of normal, serum bilirubin > 34.2mmol/L);renal dysfunction (serum creatinine > 120mmol/L; se-rum urea nitrogen > 6.4 mmol/L); other clinically sig-nificant abnormalities in prestudy laboratory tests; abnor-mal electrocardiogram, abnormal cardiac wall motionejection fraction, or arrhythmias requiring drug treat-ment; history of significant neurologic or psychiatric ill-ness; presence of otherwise severe concurrent illness thatwould render the patient unstable during the trial.

Study Procedures

Within 72 hr before administration of the study druginformed consent was obtained, a medical history wastaken, and patients underwent physical examination,clinical laboratory tests, pregnancy test (if appropriate),assessment of vital signs, and a supine 12-lead ECG. Inaddition, patients were evaluated with respect to theirprevious history of nausea and episodes of vomiting andretching. Patients who met the eligibility criteria wereassigned a number in sequential order and entered intothe study.

Dolasetron 0.6 mg/kg, 1.2 mg/kg, 1.8 mg/kg, or 2.4mg/kg was diluted to a total volume of 30 mL and in-

TABLE I. Definition of Moderately or HighlyEmetogenic Chemotherapy

Moderately emetogenic (if not combined with a highlyemetogenic agent)

Carboplatin$300 mg/m2

Cisplatin$20 mg/m2 and <50 mg/m2

Cyclophosphamide$600 mg/m2 and <1 g/m2

administered in combination with another agentDoxorubicin$30 mg/m2 and <75 mg/m2

as a single agent or$25 mg/m2 in combinationwith another agent

Epirubicin $75 mg/m2 as a single agentor $50 mg/m2 in combinationwith another agent

Methotrexate$1,000 mg/m2

Ifosfamide >1.5 g/m2 and <3.0 g/m2

5-Fluorouracil >1 g/m2

Carmustine < 200 mg/m2

EtoposideCytarabine <1 g/m2

Highly emetogenicCisplatin$50 mg/m2

Nitrogen mustardDacarbazine$500 mg/m2

ActinomycinCyclophosphamide$1 g/m2

Cytarabine$1 g/m2

Lomustine$60 mg/m2

Ifosfamide$3 g/m2

Daunomycin$45 mg/m2

StreptozotocinAmsacrineCarmustine$200 mg/m2

MelphalanDoxorubicin$75 mg/m2

100 Coppes et al.

fused with an intravenous volumetric microdrip pumpover 10 min. Residual dolasetron was then flushed fromthe intravenous tubing with 30-mL saline infused over 5min for a total infusion time of 15 min. The end of the5-min flushing interval was defined as the start of the24-hr posttreatment phase. Chemotherapy was adminis-tered 30 min after the end of the treatment phase. Patientswere taken off study and allowed to receive escape an-tiemetic therapy if they experienced three or more emeticepisodes. During the 24-hr posttreatment phase, the useof any 5-HT3 antagonist was strictly prohibited.

The first dose to be utilized was 0.6 mg/kg. Beforeescalating to each subsequent dose level, results from theefficacy and safety evaluations were to be examined fromthe previous dose level. In the event that any given doselevel demonstrated clear subtherapeutic effect in the firstfew patients and good patient tolerance, the investigatorshad the option to escalate to the next highest dose withoutcompleting the planned 12 patients per dose level. In theevent that 0.6 mg/kg was to be found ineffective, theinvestigators had the option to allocate patients to the1.8-mg/kg dose group without testing the 1.2-mg/kg doselevel. In the event that 0.6 mg/kg was to be found highlyeffective, the investigators were to evaluate the dose of0.3 mg/kg.

Vital signs and supine 12-lead ECGs were recorded 1hr after the end of the treatment phase. During the 24-hrposttreatment phase, nausea and episodes of vomitingand retching, concomitant medications, and adverseevents were assessed every 6 hr. At 24 hr posttreatment,patients underwent a physical examination, clinical labo-ratory tests, assessment of vital signs, and a supine 12-lead ECG.

Because dolasetron is cleared rapidly from plasma andcontributes minimally to the therapeutic activity of thedrug, the pharmacokinetics of the major active metabo-lite, MDL 74,156, were evaluated for this study. Bloodsamples were taken just before the beginning of infusion,and at 0.08 (5 min), 0.5, 1, 2, 4, 6, 9, 15, and 24 hr afterthe end of the dolasetron infusion.

Evaluation of Efficacy

Efficacy was evaluated throughout the 24-hr posttreat-ment phase and was based on the number of emetic epi-sodes reported and the time to the first emetic episode oruse of escape antiemetic therapy. Treatment outcomewas assessed as complete response (defined as no emeticepisodes), major response (one or two emetic episodes),or treatment failure (three or more emetic episodes and/oruse of escape antiemetic therapy).

Evaluation of Safety

Safety was evaluated on the basis of the occurrence ofadverse events; treatment-emergent ECG intervalchanges (PR, QRS, QT, QTc, and ST); changes from

pretreatment to 24 hr posttreatment in clinical chemistry,hematology, and urinalysis measures; and changes frompretreatment to 1 and 24 hr posttreatment in vital signsmeasurements. All ECGs were initially read onsite andsubsequently analyzed by Dr. Gow, an independent pe-diatric cardiologist expert.

Pharmacokinetic Evaluation

Plasma samples were analyzed for MDL 74,156 usinga validated high-pressure liquid chromatography (HPLC)thermospray mass spectrometry/mass spectrometrymethod [20]. MDL 74,156 and trazodone (internal stan-dard) were separated from plasma by liquid/liquid ex-traction with methyl-t-butyl ether. The sample was in-jected into liquid chromatograph coupled by a ther-mospray interface to a triple quadrapole massspectrometer with selective reaction monitoring capabili-ties. An octadecyl base-deactivated (C18–d8) column wasused to separate drug from internal standard. The limitsof MDL 74,156 plasma concentration detection were 0.5to 500 ng/mL. The range for mean accuracy of the qual-ity assurance samples was 96.6% to 102%, with a rangeof mean precision of 7.6% to 9.8%. Plasma concentra-tions < 0.5 ng/mL were treated as zero concentrations forthe calculation of the mean concentrations.

Data Analysis

All patients who received the study medication duringthe trial were included in the analysis of efficacy andsafety. For quantitative variables, the comparability ofthe treatment groups at baseline was evaluated with aone-way analysis of variance on ranks controlling forinvestigator. Categorical variables were compared usinglikelihood ratio chi-square test. Because the sample sizewas too small to support inferential statistics, descriptivestatistics were prepared for the primary efficacy end-point, complete response, as well as for the secondaryendpoints, major response, complete-plus-major re-sponse, treatment failure, and time to first emetic episodeor use of escape antiemetic therapy. The results of safetyevaluations were summarized by treatment groups.

Pharmacokinetic parameters for MDL 74,156 werecalculated from plasma MDL 74,156 concentration-timedata by model-independent methods. Estimated pharma-cokinetic parameters include maximum plasma concen-tration (Cmax), time to maximum plasma concentration(tmax), area under plasma concentration-time curve to in-finity (AUC0–`), half-life (t1/2), and apparent clearance(Clapp). Descriptive statistics (mean, standard deviation,coefficient of variation) were computed for pharmacoki-netic parameters. Linear least square regression analyseswere used to relate apparent clearance to patient’s ageand to dose. The correlation coefficient for the regressionanalyses was determined. Because blood samples werecollected at time intervals beginning at the end of the

Dolasetron Antiemesis 101

infusion of dolasetron, collection times were adjusted tocompensate for the duration time of the infusion (ap-proximately 15 min) prior to the calculation of pharma-cokinetic parameters.

RESULTSPatients

Forty-six patients were enrolled at five Canadian In-stitutions (Alberta Children’s Hospital, Calgary, Alberta;Hopital Sainte Justin, Montre´al, Quebec; Hospital forSick Children, Toronto, Ontario; Janeway Child HealthCentre, St-John’s, Newfoundland; and the Children’sHospital, Hamilton Health Sciences Corporation, Ham-ilton, Ontario). Evaluation of the first 10 patients given0.6 mg/kg demonstrated a complete response in only10% of patients, with one child vomiting >50 timesthroughout the 24-hr posttreatment phase. Following theguidelines of the protocol, the dose was immediately es-calated to 1.2 mg/kg. As a result, only 10 patients re-ceived dolasetron mesylate 0.6 mg/kg. Subsequently, 12patients were enrolled at each of the remaining three doselevels.

The median age of the study population was 11.0years (range, 3.0–17.0). Twenty-nine (63%) participantswere male. The treatment groups were similar at baselinewith respect to most demographic characteristics (TableII). However, a smaller proportion of patients in the 2.4-mg/kg group had a Karnofsky score$90% than in theother three groups, and a smaller proportion of patients inthe 1.8-mg/kg group had previously experienced chemo-therapy-related nausea and vomiting than in the other

three groups. In addition, the 0.6-mg/kg and the 2.4-mg/kg group had fewer patients receiving moderately emeto-genic chemotherapy than the 1.2-mg/kg and the 1.8-mg/kg group (Table II).

Efficacy Evaluations

A complete response was achieved in 1/10 (10%) pa-tients in the 0.6-mg/kg group, 3/12 (25%) in the 1.2-mg/kg group, 8/12 (67%) in the 1.8-mg/kg group, and 4/12(33%) in the 2.4-mg/kg group. One patient in the 1.2-mg/kg group who did not experience emetic episodes,but did experience nausea, was given dexamethasone atthe mother’s insistence. As a result of this protocol vio-lation (administration of a drug considered an escapemedication), this patient was classified as a treatmentfailure. The percentage of patients with treatment failurewas 60%, 50%, 17%, and 50% in the 0.6-, 1.2-, 1.8-, and2.4-mg/kg group, respectively. The median number (andrange) of emetic episodes per dose groups was 4 (0–54),1 (0–6), 0 (0–3), and 2 (0–5) for those receiving 0.6, 1.2,1.8, and 2.4 mg/kg, respectively. Similarly, the mediantime to first emetic episode or use of escape medication(and range) for the same four dose groups was 6.8 hr(0–23.2), 7.3 hr (1.3–22.0), 8.3 hr (6.8–10.8), and 4.9 hr(1.1–17.3).

Safety Evaluations

Adverse events were generally mild to moderate inintensity and their frequency was not related to dose. Themost frequently reported adverse events were tirednessand headache; less frequent adverse events included di-arrhea, drowsiness, and fever. There were no serious ad-

TABLE II. Demographic and Baseline Characteristics of Pediatric Patients Treated With Single IV Doses of 0.6, 1.2, 1.8, or 2.4mg/kg of Dolasetron

Variable

Dolasetron (mg/kg)

0.6(n 4 10)

1.2(n 4 12)

1.8(n 4 12)

2.4(n 4 12)

Total(n 4 46)

Median age, years (range) 11.0 (7.0–17.0) 10.0 (3.0–16.0) 12.5 (4.0–16.0) 10.5 (4.0–16.0) 11.0 (3.0–17.0)Gender [n (%)]

Male 7 (70) 8 (67) 8 (67) 6 (50) 29 (63)Female 3 (30) 4 (33) 4 (33) 6 (50) 17 (37)

Race [n (%)]Caucasian 9 (90) 12 (100) 11 (92) 10 (83) 42 (91)Black 0 (0) 0 (0) 0 (0) 1 (8) 1 (2)Other 1 (10) 0 (0) 1 (8) 1 (8) 3 (7)

Weight (kg), mean ± SD 38.9 ± 16.7 39.0 ± 16.8 39.8 ± 16.6 37.4 ± 15.3 38.7 ± 15.8Height (cm), mean ± SD 151 ± 24 141 ± 27 135 ± 37 136 ± 19 140 ± 27Karnofsky Status (%),a median (range) 90 (75–100) 90 (75–100) 90 (90–100) 80 (60–100) 90 (60–100)Total accumulated dose of

anthracycline (mg/m2) 281 ± 125 229 ± 153 154 ± 90 147 ± 141 200 ± 136Previously experienced chemotherapy-related

nausea and vomiting, n (%)a,b 9 (100) 10 (100) 7 (64) 9 (90) 35 (88)Emetogenicity, moderate/high (n) 5/5 10/2 10/2 6/6 31/15

aSignificantly different atP < 0.05.bPercentage calculated over number of patients who had previously received chemotherapy; SD4 standard deviation.

102 Coppes et al.

verse events or deaths during the study, nor did any patientswithdraw from the study prematurely for any reason.

Changes from baseline in clinical laboratory param-eters were observed posttreatment in all treatmentgroups, but the small number of patients in each groupprecluded detection of trends across doses. The changesobserved were likely related to intravenous hydration,chemotherapy, cancer-related factors, and stress.Changes from baseline were also noted in vital signsmeasurements, but these changes were not dose-relatedand were without clinical consequence. Assessment ofphysical examination findings revealed no apparent sys-tematic changes from pretreatment.

Evaluation of ECGs at 1 hr posttreatment revealedasymptomatic increases from pretreatment in the PR,QRS, QT, and QTc intervals in all groups; the increaseswere dose-related for the PR and QRS intervals. Changesfrom baseline at 24 hr were smaller than those at 1 hr forvirtually all determinations. No torsades de pointe and noventricular arrhythmias were reported. The treatment-emergent ECG effects occurred at all four dose levels butwere asymptomatic, generally mild in intensity, and notconsidered of clinical significance.

Pharmacokinetic Evaluations

Mean pharmacokinetic parameters for MDL 74,156are summarized in Table III. Following a single IV in-fusion of dolasetron from 0.6 to 2.4 mg/kg, MDL 74,156appeared rapidly in plasma with peak concentrations ob-served between 0.33 and 0.75 hr after the start of dolas-etron administration; mean tmax values ranged from 0.41to 0.61 hr. The Cmax of MDL 74,156 increased withlarger doses, as did the mean AUC0– values. The meant1/2 was approximately 5 hr for all doses. Finally, themean Clapp, ranging from 14.29 to 18.83 mL/min/kg, wasindependent of dose, and tended to decrease linearly withincreasing patient age (range, 3–17 years).

DISCUSSION

Studies in adults have consistently demonstrated thatan intravenous dose of 1.8-mg/kg dolasetron is more ef-

fective than doses of 0.6, 1.2, or 2.4 mg/kg [13,21,22]. Inaddition, preliminary data in adults suggest that a singleintravenous dose of dolasetron is more effective thanmultiple smaller doses [14]. Meanwhile, these studieshave demonstrated that the safety profile of dolasetron iscomparable to other selective 5-HT3 antagonists such asondansetron, granisetron, and tropisetron [7,23]. Verylittle information, however, was available on the poten-tial utility and safety of dolasetron in children [18].

Because this trial was the first time that escalatingdoses of dolasetron were being used in a pediatric popu-lation, we elected an open-label, dose-escalating studyrather than a randomized, double-blind design. Our firstobjective was to assess a possible dose response and oursecond one to evaluate the safety and efficacy of intra-venous dolasetron at the four dose levels utilized. Analy-ses were done using descriptive statistical techniquesonly, since the sample size was too small to supportinferential statistics. The response rates over 24 hr in thisstudy were within the range of those reported in studiesof children undergoing moderately to highly emetogenicchemotherapy who received single-agent treatment withother 5-HT3 antagonists [24–27].

Our results suggest increased efficacy of dolasetron upto a single intravenous dose of 1.8 mg/kg. Eight of 12(67%) patients treated at this dose level remained com-pletely free of emesis over the 24-hr study period. Wenoted that the proportion of patients that had experiencednausea and vomiting during previous cycles of chemo-therapy was lower in the 1.8-mg/kg group than in theother three groups. Since this is a factor known to pre-dispose to an unsatisfactory response to antiemetictherapy during subsequent cycles of treatment [28], wehypothesized that this could have influenced our results.However, of the eight patients who had a complete re-sponse in the 1.8-mg/kg group, six (75%) had previouslyexperienced chemotherapy-related nausea and vomiting.Thus, the greater antiemetic effect of the 1.8-mg/kg dosedid not appear to be related to the imbalance at baselinein the proportion of patients who had previously experi-enced chemotherapy-induced nausea and vomiting.

The overall low complete response rate in the 0.6-mg/kg

TABLE III. Mean Pharmacokinetic Parameters of MDL 74,156 Following Treatment WithSingle IV Doses of 0.6, 1.2, 1.8, or 2.4 mg/kg of Dolasetron

Pharmacokineticparameter(mean ± SD)

Dolasetron, mg/kg

0.6(n 4 10)

1.2(n 4 12)

1.8(n 4 12)

2.4(n 4 12)

Cmax (ng/mL) 135.50 (32.65) 315.97 (108.40) 538.17 (240.56) 738.71 (394.37)tmax (hr) 0.41 (0.18) 0.52 (0.19) 0.47 (0.21) 0.61 (0.21)AUC0– (hr ? ng/mL) 450.64 (166.46) 949.36 (341.93) 1,881.66 (989.87) 2,730.86 (1,987.37)t½ (hr) 4.80 (1.19) 4.60 (1.62) 4.98 (0.92) 5.13 (2.03)Vapp(L/kg) 7.43 (2.14) 6.80 (3.67) 5.89 (1.92) 5.91 (2.45)CLapp (mL/min/kg) 18.83 (7.76) 17.17 (5.01) 14.29 (5.47) 14.65 (6.33)

Dolasetron Antiemesis 103

group (10%) and the severity of emesis noted in onepatient entered at this dose level led to the early closureof this arm. We concluded that this dose level is inap-propriate for the management of nausea and vomiting inchildren. This dose level is also less effective in adultpatients receiving chemotherapy [23]. In the remainingtwo dose levels studied, treatment failure was noted inapproximately half of patients. Since the distribution ofmoderately vs. highly emetogenic chemotherapy admin-istered to patients in the 1.2-mg/kg group was similar tothe 1.8-mg/kg group, the 1.8-mg/kg dose level wouldseem to possess superior antiemetic efficacy. With regardto the 2.4-mg/kg group, the relatively high proportion ofpatients with a Karnofsky status <90% may have influ-enced the study outcome. Patients in the 2.4-mg/kg groupmay have been more ill and therefore more difficult tomanage. This could explain the poorer results in thisdosage level compared to the 1.8-mg/kg group, althougha decreased effect with 2.4 mg/kg has also been noted inadults [13,22,23].

As in adults, MDL 74,156, the reduced metabolite ofdolasetron, appeared rapidly in the plasma of pediatriccancer patients. Mean Cmax and tmax values in this studywere comparable to values in a population of normalhealthy adult males [29] suggesting similar rates of MDL74,156 formation. While higher mean Clapp rates andshorter t1/2 times were found in the pediatric cancer pa-tients compared with the normal subjects, similar ratiosof mean t1/2 and Clapp values suggest that the observeddifferences between the two populations were due tofaster elimination of MDL 74,156 and not to reducedformation rate or the extent of MDL 74,156 in the pedi-atric cancer patients. In the pediatric cancer patients,Cmaxand AUC increased with larger doses of dolasetron,while no dose-related trends were found for t1/2 andClapp.

All adverse events occurring during this study weremild to moderate in intensity. As in previous dolasetronstudies [14,15,23,30,31] and other 5-HT3 antagonists tri-als [32,33], tiredness and headache were the most com-monly reported adverse events. As in previous studieswith 5-HT3 receptor antagonists [3,13,15,22,23,31,32,34], we also noted asymptomatic changes in ECGintervals. None was of clinical consequence or requiredmedical treatment.

Results from this study are similar to those in larger,randomized, double-blind studies in adults. All doseswere well tolerated and adverse event profiles were simi-lar to those observed in adults. Increased clearance andcomparable Cmax and tmax values suggest that no doseadjustment is necessary in a pediatric population. Evalu-ation of the percentages of patients with complete ormajor response, the number of emetic episodes, and thetime to first emetic episode or escape therapy yieldedcomparable findings. For all of these parameters, the re-

sponse to treatment was greatest in the 1.8-mg/kg group.While a definitive comparison was not possible in thisstudy, given the small number of patients treated at eachdose level and the variation in emetogenic chemothera-peutic agents administered to each child, we have electedthe 1.8-mg/kg dose level for a randomized double-blindcomparative trial in children to evaluate and compare theefficacy of intravenous dolasetron mesylate (1.8 mg/kgas a single dose) and intravenous ondansetron (0.15 mg/kg every 8 hr for 24 hr) when both are used in combi-nation with intravenous dexamethasone.

ACKNOWLEDGMENTS

We thank Dr. Robert Gow, Department of Cardiology,Hospital for Sick Children, Toronto, Ontario, Canada, forreviewing all electrocardiograms, ensuring consistencyamong electrocardiogram readings and the identificationof treatment emergent changes. We also acknowledge hisvaluable review of this article.

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