FORMULARY FORUM

ONDANSETRON: A SEROTONIN RECEPTOR (5-HT a) ANTAGONIST FOR ANTINEOPLASTIC CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING David R. Kohler and Barry R. Goldspiel

ABSTRACT: Ondansetron represents a new class of drugs that exert their antiemetic activity by selective inhibition of a serotonin receptor subtype (5-HT,). Ondansetron has marked activity against emesis associated with cisplatin and other highly emetogenic drugs. Compared with high doses of metoclopramide. the antiemetic "gold standard." it demonstrates equal or superior efficacy. Although ondansetron is moderately well absorbed after oral administration. only a parenteral formulation will initially be available. Ondansetron is eliminated almost entirely by hepatic metabolism; less than five percent of an intravenously administered dose is recovered intact in urine. The half-life of ondansetron is approximately 3.5 hours; slightly shorter in children and prolonged in the elderly. Neither clinical efficacy nor adverse effects have correlated with serum concentrations. Ondansetron is generally well tolerated. Clinically relevant adverse effects include headache. diarrhea or constipation. sedation. and transient minor elevations of liver function tests. It is not associated with extrapyramidal reactions. Ondansetron is indicated as prophylaxis for nausea and vomiting associated with emetogenic chemotherapy. Studies to further evaluate and define its use are ongoing.

HO

N SEROTONIN

Dlep Ann Pharmacother 1991;25:367-80.

ONDANSETRON

and understanding the etiologies of emesis and recent development and better definition of the roles for drug prophylaxis, it is estimated that approximately 30 percent of patients receiving antineoplastic chemotherapy still experience acute nausea and vomiting. 1 The discovery of each neurochemical component implicated in contributing to the emetic reflex has prompted the development of specific pharmacologic antagonists. However, the mechanisms by which cytotoxic agents activate an emetic response, whether there is consistency in the neurochemical events that are prerequisite to clinical emesis, or whether there is some degree of specificity in how drugs stimulate emesis remain unclear. Progress in pharmacologic control of iatrogenic emesis has been limited by adverse effects associated with the more active antiemetic agents. Newer drugs with different pharmacologic activities offer the potential to eliminate extrapyramidal reDESPITE STRIDES TOWARD IDENTIFYING

DAVID R. KOHLER. Pharm.D .. and BARRY R. GOLDSPIEL, Pharm.D .. are Oncology Clinical Pharmacy Specialists. Department of Pharmacy. Warren G. Magnuson Clinical Center, Bldg. 10. Room IN-257. Bethesda. MD 20892. Reprints: David R. Kohler. Pharm.D. Ondansetron (Zofran), Glaxo Inc.

This article is approved for continuing education credit.

Figure I. Graphic formulas of serotonin and ondansetron.

actions, a major adverse effect of dopaminergic receptorblocking drugs. They also offer the potential to improve emetic control and diminish cumulative toxicity formerly observed when drugs that possess similar adverse effect profiles were combined. Ondansetron has recently undergone intensive investigation in Europe and in the U. S. (Figure 1). Its approval by the Food and Drug Administration (FDA) heralds the appearance of a new class of antiemetic agents that promise to provide major control of nausea and vomiting associated with cytotoxic chemotherapy while producing relatively fewer adverse effects than drugs that are currently available. Pharmacology

The pathophysiology of chemotherapy-induced nausea and vomiting is a complex, coordinated, physiologic process involving several organ systems and neurotransmitters (Figure 2). The chemoreceptor trigger zone (CTZ) is located in the area postrema of the fourth ventricle, one of the paraventricular areas of the brain. Because it lies outside of the blood-brain barrier, it is accessible to stimulation by drugs and chemicals circulating in the blood and cerebro-

D1ep, The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

1991 April. Volume 25 •

367

spinal fluid. Dopaminergic receptors have been identified in the CTZ and this observation has been used therapeutically. as many of the currently available antiemetic agents are dopamine antagonists. 2.J The emetic center. located in the lateral reticular formation of the medulla, is the common pathway proposed to coordinate the actions of the gastrointestinal (GI) tract, diaphragm, and other respiratory muscles to produce nausea and vomiting. The vestibular and labyrinthine apparatus, cerebral cortical structures, and the periphery provide afferent stimuli that may also activate the emetic center. The vestibular apparatus, although linked to the emetic center, is primarily involved with nausea and vomiting associated with motion-sickness. Higher cortical structures have been etiologically linked with nausea and vomiting, particularly in association with anticipatory nausea and vomiting phenomena. Peripheral stimulation of the emetic center occurs through activation of receptors along the GI tract that transmit afferent impulses to the emetic center primarily via the vagus nerve. Dopamine and, more recently, serotonin receptors have been identified in the periphery and are implicated in contributing to emet-

ogenesis.' Serotonin or 5-hydroxytryptarnine (5-HT) is a ubiquitous neurotransmitter found in neurons of the central and periph-

eral nervous systems and in relative abundance in enterochromaffin cells of the intestinal mucosa." It was discovered more than 40 years ago and so named because of its ability to increase blood vessel tone. 5 Serotonin influences many organs involving the cardiovascular. GI, and central nervous systems and has been etiologically implicated in many clinical disorders including headache, anxiety, depression, and emesis. Serotonin exerts its effects by acting on specific receptors. At least three primary types of 5-HT receptors have been identified and several subtypes have been proposed. 6.7 The 5-HT3 receptor subtype (formerly called "M" and also called "S3") has been identified on neuronal tissue in the upper GI tract and in the area postrema of the brain.v'" Activation of the 5-HT3 receptor that may be coupled to cation channels causes rapid membrane depolarization. 7.10 Cubeddu et al. demonstrated an increased excretion of urinary 5-hydroxyindoleacetic acid, the primary metabolite of serotonin, in patients receiving cisplarin-based chemotherapy. II The patients' platelet concentrations of serotonin were not affected, suggesting that the major source of increased circulating serotonin was derived from the other large pool of 5-HT in humans, the GI tract. This finding suggested an additional theory regarding the mechan-

4th

J

(area postrema)

ventricle of the brain

IV cytotoxic +-drugs

vasoconstriction airway _ 1 -_ _ ...., secretion tachycardia

systemic circulation abdominal vagus

tachyantria+-tI~-

intestinal wall

ingested _ _---' toxins

---1

Jlumen

Figure 2. The neurophysiology of the emetic reflex. The vomiting center is envisioned as the regions in the brainstem that integrate the emetic response. The heavy black arrow located on the left of the figure represents interactions between the vomiting center and visceral and somatic motor nuclei that subserve systems indicated by the prodromal signs and symptoms of vomiting. It has been proposed that cytotoxic therapy stimulates the synthesis and release of neuroactive agents (e.g .. serotonin) in the gut that may initiate or contribute to an emetic response. indirectly by sensitizing or activating gastrointestinal or hepatic axons that carry afferent impulses to the vomiting center. or directly by stimulating the chemoreceptor trigger zone (CTZ). Adapted from Reference 2. Used with permission of the authors and the publisher. Elsevier Science Publishers.

368

•

DlCP, The Annals ofPharmacotherapy

•

1991 April, Volume 25

Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

Ondansetron

Several investigators have used the ferret as an animal model for chemotherapy-induced vomiting to demonstrate the antiemetic properties of ondansetron. Similar experiments had demonstrated the efficacy of high-dose metoclopramide (HD-MCP) as an antiemetic. Intravenous or intraperitonealinjectionof ondansetron successfully blockedretching and vomiting in ferrets induced by intraperitoneal administration of cisplatin."-" Also, direct injection into the area postrema produced a brief, dose-related inhibition of vomiting induced by cisplatin, cyclophosphamide, or ionizing radiation.v-"

ism of chemotherapy-induced vomiting. namely, that antineoplastic agents or their metabolites cause serotonin release from enterochromaffin cells. Local high concentrations of serotonin then activate the 5-HT J receptors located on visceral afferent fibers to stimulate the crz, the emetic center, or both, to produce emesis. The discovery of serotonin receptors and development of specific receptor antagonists has provided an additional mechanism and direction for therapeutic intervention in antineoplastic-induced emesis. Actions of serotonin can be blocked by administration of specific receptor antagonists. 12·14 Ondansetron, known investigationally as GR-C507175 and GR38032F, is chemically: (±) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lHimidazol-l-yl)methyl]-4H-carbazole-4-onemonohydrochloride dihydrate (Figure I). Ondansetron is a potent and selective 5-HT J receptor antagonist."-" Its selective affinity ratio for 5-HTJ receptors compared with "5-HT,like" and 5-HT2 receptors is > 1000:l.u It has negligible agonist or antagonist activity at alpha- and beta- (subtypes one and two) adrenergic receptors, no activity at histaminergic receptors (type one), and weak antagonism at histaminergic type-two receptors at high concentrations. It does not block dopamine-mediated responses in vivo." Selective 5-HTJ antagonism is demonstrated by inhibition of the von Bezold Jarisch reflex, that manifests as bradycardia and hypotension in response to activation of 5-HT r sensitive vagal afferent neurons in cardiac tissue. The reaction can be simulated in animals by intravenous injection of the selective 5-HT J agonist, 2-methyl-5-hydroxytryptamine. Ondansetron causes dose-dependent inhibition of the von Bezold Jarisch reflex in several animal models. IS

Pharmacokinetics/Pharmacodynamics The pharmacokinetics of ondansetron are summarized in Table 1. The absolute oral bioavailability of ondansetron is approximately 60 percent (dosage formulation not specified).'6.17 Peak concentrations are obtained within 0.5-2 hours following oral administration.>" Nonlinear absorption has been demonstrated at doses> 32 mg, suggesting saturation of first-pass hepatic metabolism. IS Ondansetron distributes extensively throughout the body with a large volume of distribution, reported as 163 ± 25 L in adult patients. 17 Blumer et al. reported the volume of distribution as 2.4 Ukg in children. 19 Ondansetron is moderately bound to plasma proteins on the average of 70-76 percent. 17 Ondansetron is extensively metabolized by the liver, primarily through hydroxylation of the indole ring, and to a lesser extent by N-demethylation. Sulfate and glucuronide conjugates are then formed from these intermediates.Pr"

Table 1. Summary of Pharmacokinetic Studies Cmu

T....

n

(ug/L)

(h)

tV:! (h)

8 mg iv

16

8 mg iv+ I rng/h X 23.75 h

15

8 mg po

16

18 16 16 12 12 12 12 12 16 16 6 6 6

95.6 (75.8-120.6) 125.2 (106.7-146.9) 31.2 (25.6-38.1 ) 38.9 (31.2-48.4) 80±33:j: 33± I \:j: 42± 16:j: 19.9 59.8 136.3 254.3 348.5 37.9 47.9 116.8±21.2§ 195.5±54.8§ 233.8±45.7§

0.3 (0.2-0.4) 0.3 (0.2-0.4) 1.0 (0.8-2.0) 1.0 (0.8-1.5) 0.12±0.05:j: 1.2±0.4:j: 1.1±0.3:j: 1.5 1.5 1.2 1.3 1.4 1.6 1.5

3.5 (2.7-4.2) 3.7 (3.4-4.0) 3.2* (2.4-5.8) 3.3t (3.3-8.1) 2.8±0.6:j: 3.2±0.7*:j: 3.3±0.8H 2.5 3.4 3.8 4.2 4.2 2.9 3.5

12

244± 11M

0.25

3.9±1.0:j: (2.5-6.6)

REF.

16

DOSE

8 mg po tid X 5 d 17

18

21

22

8 mg iv 8 mg po 8 mg po tid 8 mg po SO 16 mg po SO 32 mg po SO 48 mg po SO 64 mg po SO 8 mg po q 12h X 21 d day I day 21 8 mg IVB+ I rng/h x Zd h 10 mg IVB+2 mg/h x Zj h 12 mg IVB +4 rng/h X 23 h 0.15 mg/kg iv q2h X 3 doses/d x 5 d day I

16

AUC

CI...

(f.LglL per h)

(Uh)

229.4 (209.2-251.6) 885.1 (804.1-974.2) 133 (106.7-165.6)

34.7 (31.6-38.1 ) 36.1 (32.8-39.7)

CI"na' (Uh)

0.6 (0.4-0.9) 1.0 (0.8-1.3) I.l

(0.8-1.4) 0.9 (0.7-1.3) 42.1±10:j: I.2±O.M I.l ±0.6:j:

101.5 337.8 590.9 1323.6 1941.9 178.2 208.9 1595.9±260.0§ 2841.3±605.1§ 4195.1 ±850.2§

50.8 44.8 16.53 ± 2.1O§ 20.63 ± 3.62§ 3 1.59 ±9.03§

1590± 1040:j: (826-4387)

23.9±8.MI (7.7-39.4)

*n= 14. tn=9. :j:Mean::!: standard deviation. §Mean::!: standard error of the mean. llHarmonic mean z jackknife standard deviation. AVC = area under the plasma concentration versus time curve extrapolated to' infinity; Cmo•= peak plasma concentration; CI,eno' = renal clearance; Cl••• = total body clearance: IVB = intravenous bolus: SO = single dose; tV:! = elimination half-life: Tmo. = time of peak plasma concentration.

DICP. The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

1991 April, Volume 25 • 369

Ondansetron metabolites are excreted in the urine and feces with 44-53 percent recovered in the urine within 24 hours." Renal clearance accounts for less than five percent of total body clearance of the unchanged drug after intravenous dosing. 16.17 Smith et al. reported that the area under the plasma concentration versus time curve did not correlate with plasma clearance, an observation suggestive of nonlinear pharmacokinetics. 21 Ondansetron's elimination half-life is approximately 3.5 hours in normal volunteers.w" Several investigators have reported a slightly prolonged half-life and decreased. clearance in cancer patients. 16.22.23 Lazarus et al. studied 12 cancer patients receiving cisplatin 40 mg/rrf per day for five days in combination with etoposide, carmustine, or etoposide plus carmustine. Ondansetron 0.15 rug/kg was given as an intravenous injection q2h for three doses on each day of chemotherapy. The reported half-life was 3.9 hours, slightly higher than that in normal volunteers. Mean plasma clearance was 23.9 LJh on day I, slightly lower than the values reported for normal volunteers. Pharmacokinetic parameters calculated after four consecutive days of ondansetron therapy did not differ significantly when compared with day 1 values. 22 •. . Blumer et al. reported a slightly shorter half-life In children. Nine children (aged 8-18 y) were given ondansetron 0.15 mg/kg iv q4h for three doses during chemotherapy. The reported half-life averaged 3.1 hours, but both the volume of distribution and plasma clearance were similar to adult parameters. 9 In contrast, elderly patients ha~e a prolonged half-life with a decreased clearance.v-" Pnestman et al. studied eight elderly patients with normal renal and hepatic function (mean age 73.5 y, range 65-84) who received ondansetron 8 mg po q8h for four days. They reported a half-life equal to 7.9 hours (range 5.6-9.1).24. A correlation between achieved plasma concentrations ' 1y demonstratd and response has not been cone 1usrve e .21•23 This may be a reflection that plasma concentrations do not correlate with tissue concentrations or the amount of drug bound to receptor sites. Vineret al. were unable to show increased efficacy by increasing the dose of ondansetron from 32 to 84 mg and suggested that no dose-related response could be found at the concentrations studied." One study suggested that concentrations>30 fJ.g/L maintained for 72 hours after cisplatin administration produce the best re-

sponse."

.

Although it is likely that renal dysfunction would not .be expected to alter the pharmacokinetics of o~dans.etron s~g­ nificantly, no studies have been completed In patients With renal impairment. Similarly, although it is suspect~d that drugs that either induce or inhibit hepatic P-450 microsomal enzymes may alter ondansetron's elimination, no modifications in either the dose or schedule of ondansetron are recommended prospectively for patients receiving t~ose drugs. Objective data for alterations in the pharmaco~net­ ics or pharmacodynamics of ondansetron on the baSISof renal or hepatic impairment are not yet available. Therapeutic Efficacy

When evaluating the efficacy of antiemetic agents in clinical trials, it is important to note that there are differences in the usage of terms that describe antiemetic responses for both nausea and vomiting. Although the nomenclature generally is found to be the same (e.g., com370 •

Dlep, The Annals ofPharmacotherapy

•

plete, major, minor responses, failur~), the criteria fo~ definitions of response vary between tnals. Interpretation of patient responses may in some cases be further complicated by the empiric assignment of arbitrary grades of ~esponse for statistical analysis. For example, in some studies a patient who has experienced two episodes of vomiting or retching within a given period of time may be assigned the same quality of response as that achieved ~y. a patient. ~ho had not experienced either nausea or vorrutmg. A critical comparison of results between studies or ~ ge~eralizatio~ of study results is problematic. They require Interpr~tatlOn and reconciliation of disparities between confounding patient-, treatrnent- and study-specific factors, and between investigators' methods of reporting results. 26

PHASE I AND U STUDIES

Kris et al. reported the results of an open dose-r~ging study of ondansetron administered by intermit.tent Intravenous bolus injection, initiated 30 minutes prior to chemotherapy administration, and then q2h for a total of ~~e doses. Forty-four patients in cohorts of three or more Individuals who were treated with cisplatin 120 rng/rrr' received antiemetic prophylaxis with ondansetron, escalated through ten dose levels ranging from 0.04 to 0.35 mglkg per dose. Efficacy was descri~ed in. te~s .of ~pisodes of vomiting, and was graded by Its episodic Incld~~ce. An "emetic episode" (EE) was defined as any vormtmg productive of liquid, or from one to five "dry heaves" ~i.e., vomiting not productive of liquid) within any five-minute period. Episodes of nausea were neither s~ored nor ~aded. Patients were observed for a 24-hour penod following administration of their chemotherapy. 27 Complete (no EEs) and major (two or fewer EEs) an~i­ emetic responses were noted in 18of 19treatment courses In patients who had received no prior chemotherapy. Overall, 25 of 46 treatment courses (54 percent) were associated with a complete response and 35 of 46 (76 percent) were associated with a major response to ondansetron. Adverse effects observed during the trial were generally mild, and dose-limiting toxicity did not emerge over the range of doses evaluated. No dose-related adverse effects attributable to ondansetron were observed and no patients experienced extrapyramidal reactions. The investigators recommended that ondansetron should be studied further at higher doses, and given by different schedules and routes of administration. 27 Grunberg et al. studied the efficacy and safety of escalating doses of ondansetron administered to patients receivin.g cisplatin (60-120 mg/rrr') in combination with other vanably emetogenic cytotoxic agents. Forty-three of 45 patients were evaluable for efficacy and toxicity, 38 of whom had not received chemotherapy previously. Determination of efficacy included measurements of the episodic incidence and graded severity of vomiting and nausea. Ondansetron was administered by intravenous bolus injection over 15 minutes, beginning 30 minutes before cisplatin and then q4h for a total of three doses. With the exception of the initial dose, five patients were treated at each of seven escalating dose levels (0.06-0.48 mg/kg per dose) as planned. An additional group of five patients received three intravenous doses of ondansetron (0.18 mglkg per dose), but at a dosing interval of six hours. 28

1991 April, Volume 25

Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

Ondansetron

Nineteen patients (44 percent) achieved complete protection (no EEs) and 16(37 percent) achieved major protection (:52 EEs) from emesis. Additionally, 11 (26 percent) and 8 (19 percent) of 43 patients achieved complete (no episodes of nausea) and major (two or fewer hours' duration of nausea) protection from nausea, respectively, during the 24-hour observation period following administration of cisplatin-based chemotherapy. Overall, 9 of 43 patients (21 percent) received complete protection from nausea and vomiting. 28 Patients were stratified by the doses of cisplatin «100 mg/rrr' or 2=100 mg/rrf and ondansetron «0.30 mg/kg [low dose] or 2=0.30 mglkg [high dosel) they received in order to evaluate whether an association between dose and response existed. That analysis produced a statistically significant association between higher doses of ondansetron and improved antiemetic responses for both dose ranges of cisplatin. Analysis of data from patients who received low doses of ondansetron suggested an inverse correlation between dose of cisplatin administered and antiemetic response. More patients who received low doses of cisplatin achieved complete protection from emesis than did those who received high-dose cisplatin." No information was presented concerning the relative times to onset of nausea or vomiting during the first 24-hour period, the persistence of symptoms beyond 24 hours, or any correlation of the incidence or severity of nausea with the dose of ondansetron. Although the initial dose (0.01 mglkg) was found to be ineffective, each of the higher dose levels resulted in significant antiemetic protection. The investigators recommended that a dose of 0.36 mglkg q4h should be considered as the maximum dose given by that schedule in future studies. 28 Subsequently, Lane et al. evaluated the antiemetic efficacy of ondansetron administered to 125 chemotherapynaive patients who were receiving treatment with cisplatin 2=100 mg/rn". Patients received three intermittent intravenous bolus infusions of ondansetron beginning 30 minutes prior to cisplatin and then given at four-hour intervals. Patient assignment was random to one of three dose levels: 0.015 (n = 33), 0.15 (n = 41), or 0.3 mg/kg per dose (n = 38).29

A favorable (:52 EEs) response was achieved in 42,63, and 71 percent of patients treated with 0.015,0.15, and 0.3 mg/kg of ondansetron, respectively. Patients who were treated at the two higher dosages achieved a significantly greater antiemetic response than those who received the lowest dosage. Only a small incremental increase in antiemetic protection was observed at the highest dosage compared with the 0.15-mglkg dosage regimen. Additionally, an analysis of prophylaxis "failures" (patients who experienced greater than five EEs or who received antiemetic rescue drugs) suggested a trend toward fewer numbers of failures at the highest dosage as compared with the lowest. 29 Summarily, their analysis implies that patients who receive ondansetron at doses of 0.5 mglkg may derive almost maximal antiemetic protection, although the slightly greater response reported in patients who received the higher dosage may justify a trial escalation of dosage in patients who do not achieve a satisfactory or a less than optimal antiemetic response at the lower dosage. Smith et al. conducted a two-part clinical trial studying the safety and antiemetic efficacy of high doses of ondan-

setron in 24 patients, 10 of whom had previous exposure to cisplatin-containing chemotherapy regimens and had experienced nausea and/or vomiting, refractory to combination antiemetic prophylaxis. Patients received mildly emetogenic, combination, cytotoxic chemotherapy including vincristine, bleomycin, and methotrexate with leucovorin on days 1-3, followed by cisplatin 100-120 mg/m- by intravenous infusion over 12 hours on day 4. Ondansetron was administered as an intravenous bolus 30 minutes before cisplatin at doses of 8, 10, or 12 mg, followed by a continuous intravenous infusion over 24 hours at dose rates of 1,2, or4 mg/h, respectively." Patients who achieved either a complete' or major antiemetic response (i.e., two or fewer EEs) during the first phase of the study were eligible for the second part, in which ondansetron was continued orally at two dosages: 8 (n = 2) and 12 mg (n = 6). Oral therapy was started at hour 22, two hours prior to completion of the continuous intravenous infusion of ondansetron, and then given tid on days 2-5 following cisplatin. Patients were observed for the first 24 hours and were requested to maintain diary cards over the following five days." Overall, 8 of 23 (5 percent) during the first 24 hours and 2 of 8 patients (25 percent) during the following five days achieved a complete or major antiemetic response. For those who had achieved a complete or major response over the first 24-hour period, there were no differences in the incidence or quality of antiemetic responses with respect to patients' previous exposure to chemotherapy. 21 The investigators concluded that there was no improvement in ondansetron's therapeutic effect at cumulative doses>32 mg over 24 hours, and that there was no clearly defined correlation between concentrations of the drug in serum and patients' responses. 21 Hesketh et al. have reported the results of a large, multicenter trial comparing the efficacy and toxicity of two dosage schedules of ondansetron in patients receiving cisplatin 2=100 mg/nf for the first time. Patients received three fixed intravenously administered doses of ondansetron 0.18 mglkg, with random assignment to either a six- or eighthour interval between doses. Patients were observed in the hospital for 24 hours after cisplatin administration. Objective study endpoints included the number of EEs, time to emesis, and the volume of emesis. EEs were defined as single incidents of vomiting or one or more incidents of retching within a five-minute period. 30 Of 85 patients entered into the study, 15 patients' courses of therapy were excluded from comparative efficacy analysis as a result of study protocol violations. No significant differences in efficacy were noted between groups: 28 of 34 patients (82 percent) treated at six-hour intervals and 26 of 36 (72 percent) treated at eight-hour intervals achieved a complete (no EEs) or major (:52 EEs) response. By combining the efficacy data of eligible patients with that from patients whose courses of therapy were disqualified as a result of administration schedule violations into"overall antiemetic response rates," the investigators claimed an overall complete and major response rate of 75 percent. 30 Antiemetic response assessment graded by patients' recent ethanol consumption patterns demonstrated a statistically significant difference between groups. Although heavy ethanol users (greater than one drink/d) exhibited more complete emetic control (74 percent) than nonusers or oc-

DICP, The Annals ofPharmacotherapy Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

•

1991April,Volume25

•

371

casional users (less than seven drinks/wk [33 percentl), the investigators proposed that the overall antiemetic response rate for occasional and nonusers (54 percent) indicated an antiemetic benefit not merely attributable to selection of a particularly favorable demographic population. 30 Patients' subjective complaints of nausea were comparatively assessed by a linear visual analog scale (VAS). There was no statistically significant difference between groups in the degree of nausea experienced following chemotherapy. The investigators observed that patients who achieved a complete antiemetic response also experienced less nausea than those who sustained any number of EEs following their chemotherapy treatment. 30 Viner et al. evaluated the antiemetic efficacy and pharmacokinetics of two dosage regimens of ondansetron in an open study of patients receiving high doses of melphalan for multiple myeloma. Patients treated with "low-dose" ondansetron received an intravenous bolus loading dose of 8 mg, followed by an intravenous infusion of ondansetron I mg/h until hour 48. "High-dose" ondansetron patients received an intravenous bolus of 12 mg, followed by a continuous intravenous infusion of 3 rng/h for 24 hours. Twelve hours after their dose of melphalan was administered, continuous infusion of ondansetron was interrupted for one hour to allow reinfusion of bone marrow in 27 patients who received autologous bone marrow transplantation. Patients undergoing transplantation on the low- and high-dose ondansetron regimens received an additional bolus injection of ondansetron I or 3 mg, respectively, just prior to marrow reinfusion. Oral therapy was initiated at the end of the continuous infusion for both treatment groups. Low-dose patients received 8 mg q6h on days 3-7. Patients treated with high-dose ondansetron received 8 mg q8h for six days." Six patients not treated with autologous bone marrow transplantation received a lower dose of melphalan (140 .mg/rrr') compared with the preparatory dose of melphalan (200 mg/rrr') given to patients prior to transplantation. Additional treatment differences included daily administration of methylprednisolone 1500 mg for five days, beginning 24 hours after melphalan administration in patients who received autologous marrow transplantation, and a provision that allowed transplanted patients to continue oral ondansetron. Continuation of oral therapy was allowed for additional seven-day periods for a maximum duration of one month if patients experienced any nausea or vomiting after completing their initial course of ondansetron. Patients were monitored daily for efficacy and toxicity attributable to ondansetron while receiving antiemetic therapy and for assessment of nausea. 2S Overall favorable antiemetic response to ondansetron was 42 percent, including four (24 percent) and one (6 percent) complete responses (no EEs/d) and five (29 percent) and four (25 percent) major responses (one or two EEs/d) for patients who received low- and high-dose ondansetron regimens, respectively. Although there was no statistically significant difference in the incidence ofEEs between groups, the investigators provided no assessment of the incidence of nausea or emesis relative to the antineoplastic regimen administered (i.e., low-dose or high-dose melphalan plus autologous bone marrow transplantation) or its impact on antiemetic response. Z5 Fifty-eight percent of patients who did not achieve a complete or major response required alternative antiemetics. 372

•

Dlep. The Annals ofPharmacotherapy

•

Specific information about patient withdrawal was provided for only one patient, although seven over the first 24 hours and four over the seven-day study period failed to achieve a favorable antiemetic response (i.e .. greater than five EEs). Whether more than one patient may have withdrawn from the study was implied by the investigators' statement, "the only reason for withdrawal. .. was failure to respond to treatment." Because plasma concentrations of ondansetron for the patient who was specifically cited as having failed therapy were comparable to those observed in other patients with good control, the investigators concluded that for the doses studied, clinical response is not related to plasma drug concentrations." Green et al. studied the efficacy of ondansetron against the emetogenic effects of ifosfamide in two groups: patients who had received no prior chemotherapy (group A) and patients who previously had poor emetic control with HDMCP (>4 mg/kg per 24 hours [group B D. Patients in group A received ondansetron 4 mg, administered as an intravenous bolus infusion over 15 minutes, initiated just before ifosfamide and then q6h for seven total doses. Patients in group B received ondansetron by the same schedule, but at 8-mg doses. Both groups received antineoplastic chemotherapy with ifosfamide 4-6 g/rrr'. 31 Two of six patients in group A and three of six patients from group B achieved a complete antiemetic response during the study period. Three additional chemotherapy-naive patients achieved major control (one or two EEs). 31 Of interest is the time course and severity of nausea and vomiting for those patients who experienced emesis. The time to onset of patients' first EE ranged from 12to 36 hours after ifosfamide administration. One patient from group B who had achieved a complete antiemetic response and minimal nausea during the 42-hour study period developed delayed vomiting at hour 44. Severity of nausea was evaluated by patients at 24 and 42 hours after chemotherapy, using a VAS. Patients' assessment indicated that nausea was more severe at hour 42 than at hour 24. The investigators concluded that ondansetron 4 mg iv q6h effectively diminished the emetogenic effect of ifosfamide, but recommended that higher doses may be necessary for patients who have experienced cytotoxic-induced nausea and vomiting not controlled by other antiemetic agents." Kris et al. conducted three consecutive Phase II studies of ondansetron in patients receiving high doses of cisplatin (2::100 mg/rrr') in combination with other antineoplastic 'agents. Patients entered into the first two studies had not previously received antineoplastics. In contrast, the patients treated in the third study had previously received cytotoxic therapy. 32 In the first trial, the effects of ondansetron administered at a fixed dose by two different schedules were compared. Twenty patients were randomly assigned to receive ondansetron 0.18 mg/kg as an intravenous bolus either q2h or q4h (10 patients each) for a total of three doses. The results of trial one revealed a lack of schedule dependency for ondansetron when given by either schedule." The purpose of the second trial was to evaluate whether a lower dose of ondansetron provided efficacy similar to higher doses in eight patients receiving a single high dose of cisplatin. Ondansetron 0.04 mg/kg per dose was given as an intravenous bolus q2h for a total of three doses. Antiemetic control rates as determined by the number of EEs

1991 April. Volume 25

Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

Ondansetron

observed and patients' ratings of nausea or vomiting were inferior to those achieved during trial one. 32 Trial three studied the safety and efficacy of ondansetron administered intravenously at 0.15 mg/kg per dose, for up to five consecutive days. Patients received combination chemotherapy including cisplatin 20-25 mg/rrf per day and 5-fluorouracil or etoposide administered daily for four or five days. Ondansetron was administered prior to cisplatin, and then q2h for a total of three doses per day. Results supporting ondansetron's efficacy were favorable, but because the study was not a controlled comparative trial, antiemetic efficacy could only be compared with results achieved in similar trials of other antiemetics. Interestingly, the investigators noted a trend toward decreased antiemetic activity on the third or fourth day of therapy, a difference in continuity of response not previously observed for other antiemetic agents. No interpretation of this phenomenon was offered. 32 The investigators concluded that ondansetron can be safely administered to patients receiving high doses of cisplatin for one to five days. They further recommended that three doses of ondansetron 0.15-0.18 mg/kg should be administered q2h on each day of cytotoxic therapy. 32 Einhorn et al. evaluated ondansetron in patients with various solid tumors who were receiving cisplatin-based (40-50 mg/rrr' per day) combination chemotherapy for four or five consecutive days. Twenty-four patients were stratified into two groups of 12 patients, each based upon whether patients had (non-naive) or had not (naive) previously received at least one course of chemotherapy. EEs were defined as a single vomiting episode or a five-minute period of dry retching. Episodes of retching more than five minutes apart were scored as separate EEs.33 Patients received ondansetron 0.15 mg/kg iv beginning 30 minutes before administration of cisplatin and then q6h for a total of three doses. A third group of 12 chemotherapynaive patients received ondansetron similarly, but at twohour intervals. Thirty-five of 36 patients were evaluable for efficacy analysis. 33 Ten of 35 patients (29 percent) achieved a complete response (no EEs) and 18 additional patients (51 percent) experienced s2 EEs (major response) over the four- to fiveday study period. The incidence of complete responses to antiemetic therapy was greater for chemotherapy-naive patients treated at two-hour intervals (5 of 12 [42 percent]) compared with those who received ondansetron q6h (2 of 11 [18 percent]). Three patients (25 percent) who had previously received chemotherapy also achieved a complete response. The greatest number of patients to achieve a complete response during a single 24-hour period occurred on day 1. Numbers of complete responders declined over the following treatment days for all three groups of patients. Evaluation of patients' antiemetic responses on each treatment day revealed a superior response rate of chemotherapy-naive patients when complete and major response categories were combined." Werner et al. have provided preliminary evidence that ondansetron can provide continued antiemetic efficacy through multiple repeated courses of chemotherapy in previously untreated patients. Patients who had experienced two or fewer EEs during their initial treatment cycle with high-dose cisplatin (2::100 mg/rrr') while receiving antiemetic prophylaxis with intravenous ondansetron (0.14-

0.19 mg/kg per dose for three to six doses) were eligible for study. Fifty-six patients received a total of 188 courses; 136 repeated courses (median 3, range 2-10) following their qualifying course. Complete emetic responses were achieved during 68 percent of repeated courses and complete plus major responses in 85 percent of repeated courses (72 and 90 percent of total courses, respectively) overall. Of note is the investigators' observation that the incidence of pretreatment nausea was greater on retreatment than prior to initial therapy." Speculatively, that observation may indicate development of anticipatory nausea, a phenomenon for which it has been suggested ondansetron may exert a mitigating effect. 3S Two groups have studied ondansetron in pediatric patients. Carden et al. reported results of an open, uncontrolled study of ondansetron in a group of 20 pediatric patients (aged 4-18 y). All patients had previously received cytotoxic agents and were either already receiving or about to begin a combination chemotherapy regimen that included high doses of cyclophosphamide (1000 mg/rrr'). Ondansetron was administered as a single intravenous bolus at two different sequential doses. The first ten patients received treatment with ondansetron 5 mg/m? (level one, group A) and ten other patients received ondansetron 3 mg/rrr' (level two, group B). Progression to the second level was contingent upon the adequacy of the antiemetic response achieved by the patient cohort at the first dose level. Both patient cohorts received ondansetron 2,3, or 4 mg po at a dose based upon their body surface area (BSA). The first oral dose of ondansetron was given concurrently with the intravenous bolus. It was followed by 13additional doses given q8h. 36 There was no statistical analysis to compare differences in response or adverse effects between groups. Group A patients, however, appeared to have better control of nausea over the period from days 2-5 than patients in group B. Patients tolerated therapy very well. Patients' food intake was not restricted, and although 2 patients were able to tolerate only a liquid diet for one and two days following therapy, respectively, 18 of 20 patients reported normal appetites throughout treatment. Seven of 20 patients received a second course and 2 patients a third course of chemotherapy and ondansetron. Patients who received repeated courses did not report a worsening of nausea or vomiting with repeated courses. The investigators concluded that ondansetron is remarkably effective as a single agent and is associated with minimal adverse effects. 36 Pinkerton et al. studied the effects of ondansetron against acute and delayed nausea and vomiting in 30 pediatric patients (aged 2-16 y) with various solid tumors. Patients were stratified by their cytotoxic therapy into one of four groups. Comparisons were made among those patients who received carboplatin-, cisplatin-, cyclophosphamide and doxorubicin-, or ifosfamide and doxorubicin-based regimens. Ondansetron was administered as a parenteral loading dose of 5 rng/m", followed by oral maintenance doses given q8h for five days. Maintenance doses were also based upon patients' BSA. Patients with BSA 1.0 m2 received I, 2, 3, and 4 mg of ondansetron, respectively. Patients were observed inhospital for the 24-hour period following cytotoxics administration. Evaluation for days 2-5 was accomplished by means of a questionnaire. 37

Dlil]",The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

1991 April, Volume 25

•

373

Ninety-two, 88, 80, and 50 percent of patients who received carboplatin-, cyclophosphamide-, ifosfamide- and cisplatin-containing regimens, respectively, achieved a complete or major emetic response (two or fewer EEs) during the first 24 hours. Antiemetic efficacy was maintained through day 5 in patients who received either carboplatinor cyclophosphamide-containing therapies. In contrast, patients who were treated with either cisplatin- or ifosfamide-containing regimens developed significant late-onset nausea, vomiting, or retching (greater than three EEs) from 24 to 120 hours after cytotoxics administration. 37 Priestman et al. have evaluated the antiemetic effect of ondansetron in 25 patients receiving single exposures of ionizing radiation, 8-10Gy (800-1000 rad) to the upper abdomen for palliation of symptoms related to advanced cancer. Patients received ondansetron 4 mg one to two hours prior to irradiation, and then four times daily, for three days. The investigators presented preliminary data that demonstrate a complete response rate for 20-24 patients (80-96 percent) and 11-14 patients (44-56 percent) for emesis and nausea, respectively. However, the effect of ondansetron on emetogenesis due solely to radiation is difficult to interpret as two patients reported one to two EEs and five patients reported mild to moderate nausea during the 24-hour period prior to the onset of radiotherapy.38 In summary, Phase I studies have described antiemetic efficacy for ondansetron administered intravenously over a range of doses (0.06-0.48 mg/kg per dose) and administration schedules (q2-8h) in patients receiving cisplatincontaining combination chemotherapy regimens without having encountered dose-limiting toxicity. The lowest clinically effective dose, the optimally effective number of doses, and the maximally tolerated dose have not been precisely defined. In Phase II studies, ondansetron appeared to offer protection against nausea and emesis from a broad range of antineoplastic regimens and dosage schedules. It has been shown to be both safe and effective when given over several consecutive days concomitantly with multipleday chemotherapy. Neither a clinically significant relationship between dose and antiemetic response nor a correlation for efficacy or toxicity with concentrations of ondansetron in blood or serum have emerged from uncontrolled trials. Furthermore, there was no clinically significant difference in either the incidence or severity of adverse reactions between the different schedules of administration that were evaluated. COMPARATIVE TRIALS

Comparative trials (Table 2) have focused primarily on ondansetron's safety and efficacy relative to high doses of MCP, an agent with established efficacy against nausea and vomiting induced by highly emetogenic chemotherapy that constitutes the standard against which other antiemetics are compared. Of interest are the data detailing the adverse effects profiles for both agents; of particular note are comparisons between the two drugs for manifestations of extrapyramidal reactions. Cubeddu et al. studied the antiemetic effect of ondansetron compared with placebo in 28 patients who received antineoplastic therapy with cisplatin. Patients who experienced at least three EEs within a one-hour period or who required immediate intervention as a result of intense nausea or vomiting received "antiemetic rescue," a combination 374 •

Dlep. The Annals ofPharmacotherapy

•

of agents administered sequentially over 15 minutes, including diphenhydramine 50 mg, dexamethasone 20 mg, diazepam 5 mg, and MCP 2 mglkg. Patients were observed for the 24-hour period following administration of cisplatin and were requested to record any further incidents of nausea or emesis for an additional 72 hours. 11 Statistical assessment of differences in antiemetic efficacy between groups supported the clinical observation that ondansetron was superior to placebo with regard to onset of emesis, number of EEs, mean number of vomits per EE, frequency and severity of vomiting, patients' VAS assessment of the control of nausea, and their satisfaction with protection from nausea and emesis. Twelve of 14 patients who received placebo required antiemetic rescue, whereas no patient retreated with ondansetron required res-

cue." Patients who reported episodes of delayed emesis (i.e., occurring 2::24 h after cisplatin administration) characterized their experiences as very mild and limited to only one vomit per episode. Although the difference in the incidence of delayed nausea and vomiting between the treatment and control groups was statistically significant, a similar number of patients from each group experienced no emesis during the period 24-96 hours after administration of cisplatin. Eighty-five percent of patients treated with ondansetron (11 of 13) and 55 percent treated with placebo (6 of 11) had received antiemetic rescue reported experiencing at least one episode of delayed nausea and vomiting. No significant differences were observed between groups in either the incidence or severity of adverse effects. 11 Marty et al. compared the safety and antiemetic efficacy of ondansetron to HD-MCP in 97 previously untreated patients. Patients were randomly assigned to either HD-MCP or ondansetron with their first cycle of chemotherapy and subsequently crossed over to receive the alternate agent during their second cycle of antineoplastic therapy. Patients were also allowed to receive supplementary "standard" antiemetic agents on days 2-7 depending upon the practice of the participating study centers. However, patients were evaluable for efficacy assessment for both nausea and vomiting on days 2-7 only if the supplementary antiemetics they received were consistent in terms of agents used, dosage, and schedule during both treatment periods. 39 Patient responses were evaluated by the number of EEs that occurred during the 24-hour period following cisplatin administration. Patients recorded episodes of delayed-onset nausea and vomiting. The incidence and severity of patients' nausea was assessed by two indices: comparisons between their graded subjective descriptions and VAS responses before and after treatment. Statistical analysis of data derived from VAS scores revealed that the overall median increase in posttreatment nausea was significantly less for ondansetron treatment. Additionally, the incidence of severe nausea was 14 percent with ondansetron therapy compared with 29 percent during HD-MCP treatment. 39 When an interim analysis revealed that patients' antiemetic response to ondansetron was statistically superior to HD-MCP, the study was prematurely terminated. The investigators noted that although ondansetron treatment was associated with a significantly greater complete emetic control rate acutely, there was no apparent difference between groups in either the incidence or severity of delayed nausea and vomiting in patients who satisfactorily com-

/991 April. Volume 25

Downloaded from aop.sagepub.com at UCSF LIBRARY & CKM on December 4, 2014

Ondansetron

Table 2. Summary of Comparative Trials ofOndansetron REF. ANTIEMETIC REGIMEN

II

39

o 0.15 rng/kg

per dose IVB 30 minutes before CTx. then q4h x 3 total doses or P

o 8 mg IVLO. then

I

rng/h CIV x 24 h maintenance

TRIAL DESIGN

n*

acute NV: random

14

CHEMOTHERAPY REGIMEN

cOOP2:50 mg/rrr' ± other unspecified chemotherapy

14

RESPONSE CRITERIA

STATISTICAL EVALUATION

vomiting episodes: 0= 1.5; P=5.5 (median)

p