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International Scholarly Research NetworkISRN OncologyVolume 2012, Article ID 798239, 10 pagesdoi:10.5402/2012/798239

Clinical Study

Assessment of Ondansetron-Associated Hypokalemia inPediatric Oncology Patients

Elsa Fiedrich, Vikram Sabhaney, Justin Lui, and Maury Pinsk

Division of Pediatric Nephrology, University of Alberta, 11405-87 Avenue, Edmonton, AB, Canada T6G 1C9

Correspondence should be addressed to Maury Pinsk, [email protected]

Received 4 July 2012; Accepted 14 August 2012

Academic Editors: Z. Estrov and L. Mutti

Copyright © 2012 Elsa Fiedrich et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. Ondansetron is a 5-hydroxytryptamine (5-HT3, serotonin) receptor antagonist used as antiemetic prophylaxispreceding chemotherapy administration. Hypokalemia is a rare complication of ondansetron, which may be underreporteddue to confounding emesis and chemotherapy-induced tubulopathy. We performed a prospective cohort study to determine ifondansetron caused significant hypokalemia independently as a result of renal potassium wasting. Methods. Twelve patients wererecruited, with ten completing the study. Blood and urine samples were collected before and after ondansetron administration inpatients admitted for intravenous (IV) hydration and chemotherapy. Dietary histories and IV records were analyzed to calculatesodium and potassium balances. Results. We observed an expected drop in urine osmolality, an increase in urine sodium, butno statistically significant change in sodium or potassium balance before and after ondansetron. Conclusion. Ondansetron doesnot cause significant potassium wasting in appropriately hydrated and nutritionally replete patients. Careful monitoring of serumpotassium is recommended in patients with chronic nutritional or volume status deficiencies receiving this medication.

1. Introduction

Ondansetron is an antiemetic used as an adjunctive tochemotherapy in pediatric oncology patients. It is a selec-tive 5-HT3 receptor antagonist which has an excellentsafety profile and is efficacious [1, 2]. A side effect infre-quently reported is the development of hypokalemia [3].Hypokalemia may be a result of ondansetron itself [3–5], aneffect of chemotherapy on renal tubular function [6], a resultof emesis-induced alkalosis [7], or a combination of factors.

Based on in vitro data, ondansetron has the capacityto cause hypokalemia by affecting renal tubular physiology[4]. Ondansetron acts at two levels in the nephron. First, atthe level of the Loop of Henle, ondansetron downregulatesthe Na+-K+-2Cl-(NKCC2) cotransporter, which results inincreased sodium delivery to the distal nephron. This in turnnecessitates K+ excretion, via the ROMK potassium channelto facilitate the electroneutral reabsorption of sodium via theepithelial sodium channel (ENaC) from the distal nephron,leading to K+ wasting. Second, throughout the nephron,and in particular the distal tubule, ondansetron upregulates

the Na+-K+ ATPase. This exacerbates the renal K wastingby lowering intracellular sodium levels in distal tubularcells expressing ENaC thereby further increasing tubularsodium entry at this segment. This ultimately requiresincreased K secretion into the urine via ROMK to maintainelectroneutrality. Based on in vitro data, this effect on therenal tubules appears specific to ondansetron and is not acharacteristic of other selective 5-HT3 antagonists [8].

We previously described an association betweenondansetron use and the reproducible development ofhypokalemia in a pediatric oncology patient [5]. Onreview, ondansetron was recognized as a potential causativeagent. Within 24 hours of discontinuation of ondansetron,the patient’s potassium level and transtubular potassiumgradient (TTKG) returned to acceptable levels. The patientwas readmitted one month later for IV cyclophosphamidetherapy, and a single dose of ondansetron was administeredas standard anti-emetic prophylaxis. The TTKG rose to aninappropriately high level has given the patient’s volumestatus, with a concurrent drop in the patient’s plasmapotassium level.

2 ISRN Oncology

Hydration

Ondansetron given Chemotherapy given

Blood, urine tests,demographics,

physical parameters

Blood, urine tests

Diet and IV record, urine output

1–8 hours 8+ hours

Figure 1: Protocol timeline.

In that case report, we questioned whether hypokalemiarelated to ondansetron use was an underrecognized phe-nomenon due to the confounders of chemotherapy toxicityand vomiting-induced shifts in K. We therefore conducteda prospective study of patients receiving chemotherapy withondansetron to determine (1) if renal potassium wastingis a common phenomenon in pediatric oncology patientsreceiving ondansetron, and (2), if prevalent, which factorsincrease the probability of potassium wasting in pediatriconcology patients, particularly in those developing clinicallyapparent hypokalemia.

2. Materials and Methods

Based on the previous published case report, we designed aprospective cohort study to determine if hypokalemia asso-ciated with ondansetron use was an under-recognized com-plication (Figure 1). The University of AB, Canada, HealthResearch Ethics Board Biomedical Panel approved the studyprotocol. Patients were recruited sequentially and consentedinto the study from the outpatient Pediatric Oncology clinicat the Stollery Children’s Hospital in Edmonton, Albertafrom January 2008 to August 2008. Patients were selectedto participate who required administration of chemotherapywhere planned prophylactic administration of ondansetronwas expected. Chemotherapy regimens were therefore lim-ited to intravenous cyclophosphamide, cisplatin, ifosfamide,and/or high-dose methotrexate therapy. To remove anyinfluence of high aldosterone states related to intravascularvolume depletion and subsequent promotion of renal potas-sium wasting, all patients recruited into the study receivedhydration prior to the administration of ondansetron andchemotherapy. Patients were excluded from the study ifthey were unable to voluntarily provide a urine specimen,had protracted vomiting refractory to anti-emetic therapyat the time of study entry, had received ondansetron within48 hours of entering the study, or were taking potassiumsupplements for any reason. No patient had primary renalor adrenal malignancy, noted malignancy involvement of thekidneys, or diuretic use on entering the study (Table 1).

On admission, demographics including age, gender,height, weight, diagnosis, and chemotherapy protocol werecollected. In order to determine sodium and potassiumbalance for each patient throughout the pre- and posttherapystudy period, a dietary history and IV fluid record wereobtained and sodium and potassium intake and output werecalculated [9]. Before receiving the dose of ondansetron,serum samples were obtained to determine plasma osmo-lality, potassium, sodium, aldosterone, and creatinine levels.Urine samples were obtained within a few hours of theserum samples and before ondansetron administration.Urine was collected for urinalysis, osmolality, potassium,sodium, and creatinine levels. Urine volume was measuredpreceding ondansetron administration for 1–8 hours, aswell as at least 8 hours after ondansetron administration.IV hydration was administered to ensure euvolemia wasachieved prior to administration of high-dose methotrexate,cyclophosphamide, ifosphamide, or cisplatin. Patients whoshowed signs of intravascular volume depletion prior tochemotherapy administration were permitted additionalbolus intravenous normal saline to correct their volumedeficit, at the discretion of the attending oncologist. Eachpatient received at least one dose of ondansetron duringthe study period, either orally or parentally according to themanufacturer’s product monograph [3].

Four to eight hours after ondansetron therapy, serumsamples were collected to remeasure plasma osmolality,potassium, sodium, aldosterone, and creatinine levels. Sim-ilarly, urine was collected for urinalysis, osmolality, potas-sium, sodium, and creatinine.

2.1. Primary Outcomes. Primary outcome was change inTTKG. The TTKG measures the extent of potassium secre-tion in the distal portion of the tubule. It is calculated usingthe following formula:

TTKG =(

K+Urine ×OsmolalityPlasma

)(

K+Plasma ×OsmolalityUrine

) . (1)

The validity of this measurement relies on three assumptions:(1) few solutes are reabsorbed in the medullary collectingduct (MCD), (2) potassium is neither secreted nor reab-sorbed in the MCD, and (3) the osmolality of the fluid in theterminal cortical collecting duct is isoosmolar to plasma [10].The TTKG is therefore only valid when OsmolalityUrine ≥OsmolalityPlasma and urine sodium >25.

2.2. Secondary Outcomes. Secondary outcomes were (1)change in the plasma potassium, (2) change in sodiumbalance, and (3) change in potassium balance throughoutthe study interval. Balance studies were undertaken shouldthe participant’s urine be hypoosmolar relative to plasma.In short, a dietary history was used to estimate sodiumand potassium intake, in conjunction with IV fluid records.Output was assessed using urine volumes and urinary chem-istry measurements to calculate total sodium and potassiumexcreted. Balance calculations were done in both the pre-and postondansetron phase and were normalized to the time

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ISRN Oncology 7

frame of measurement and the weight of the patient toallow comparison. No patients were noted to have diarrheaor emesis throughout the course of the observation and allpatients had normal renal function.

3. Statistical Analysis

We decided that a clinically important treatment effect ofondansetron on the renal tubule would be a doubling of theTTKG and calculating the sample size based on publisheddata [5]. In that report, a single patient was observed tohave a reproducible changes in the TTKG with ondansetronexposure. The values from those clinical exposures wereused to estimate a mean TTKG before (6.2 ± 2.1) and afterondansetron (11.6 ± 2.4). We therefore used a minimumexpected difference of 5.4 with a standard deviation of 2.3.The sample size estimate for this study, using α = 0.05,a power of 90%, and assuming a parametric distributionof data, was 7.6 patients. We planned recruitment of 12patients to insure adequate sampling. Data was assessed fornormality using a one-sample Kolmogorov-Smirnov Testusing P < 0.05 as significance to reject the null hypothesisthat the distribution of each variable was nonparametric. Allvariables were assessed as parametric. As each patient actedas a pretherapy control, variables were subsequently analyzedusing a paired two-tailed Student t-test, with statisticalsignificance determined by P < 0.05.

4. Results

Twelve patients participated in the study (Table 1). Patient11 was excluded from the analysis due to inability tocollect the required urine samples. Patient 1 developedprotracted vomiting during the preondansetron phase andwas subsequently excluded. Ten patients therefore completedthe study. The patients that completed the study received2.8 ± 2.4 cc/kg/hr hydration for 7.4 ± 7.2 hours beforeondansetron and received 4.8 ± 5.4 cc/kg/hr (P = 0.30) for16.3 ± 9.0 hours (P = 0.02) after hydration. Five patientsdeveloped a urine osmolality lower than plasma osmolalityin the postondansetron phase prohibiting the calculation ofTTKG. These patients were excluded from the analysis basedon TTKG, but were included in the analysis of potassiumand sodium balance before and after ondansetron. Patient9 had elevated aldosterone levels in the postondansetronphase in the absence of hyperkalemia or acidosis (data notshown). This patient did not have stool loss during theobservation period, but was treated with a bowel enema priorto admission, suggesting an explanation for the decreasedintravascular volume and elevated aldosterone despite seem-ingly adequate prechemotherapy hydration. This patient wasincluded in the analysis.

Of the patients that completed the study, no patientdeveloped hypokalemia (Table 2). Assessment of TTKGbefore and after ondansetron did not demonstrate a signif-icant difference. Patients did develop lower urine osmolality(P ≤ 0.05) after hydration and ondansetron therapy. Afterondansetron, patients also developed an appropriately lower

urinary potassium concentration (P = 0.02) and higherurinary sodium excretion (P = 0.03). Plasma aldosteronelevels trended lower post ondansetron, but were not statisti-cally significant. Evaluation of sodium and potassium outputalso confirmed that urinary sodium was higher (P ≤ 0.05)and urinary potassium was lower (P = 0.02) in the afterondansetron phase. However, balance studies did not showappreciable differences before and after ondansetron in theseelectrolytes.

5. Discussion

We conducted a prospective cohort study of patients receiv-ing chemotherapy to determine if renal potassium wasting isa common phenomenon related to ondansetron use. We havedemonstrated that when intravascular volume contractionand preexisting tubulopathy predisposing to hypokalemiaare controlled for, ondansetron does not appear associatedwith excessive renal potassium secretion.

Renal potassium handling is, for the most part, influ-enced by two factors. First, renal tubular flow is importantin determining the quantity of potassium in the renal tubule;the faster the flow, the more likely the potassium concen-tration in the tubule will be diluted. Maintaining a lowtubular potassium concentration facilitates the secretion ofpotassium by maintaining large gradients favoring secretioninto the lumen. Low tubular flow states exist in dehydrationor with the use of angiotensin-converting enzyme inhibitorsand can lead to inability to secrete potassium and hyper-kalemia [11]. Secondly, the renal tubule needs to establishboth an electrical and a chemical gradients in the distalnephron to facilitate tubular potassium secretion. As alreadynoted, significant factors determining the magnitude of thegradient are both the amount of sodium delivery to the distalnephron, and the presence of aldosterone which facilitatesboth apical sodium entry into the cell and potassium effluxfrom the cell into the urine [12].

Our experimental design intentionally exploited a hydra-tion phase of therapy to minimize the effect of aldosterone onthe measurement of potassium in the urine. We note that thealdosterone levels did not decrease significantly throughoutthe study. We believe this is because of two reasons; first, dueto the small sample size, we included patient 9 who actuallyexperienced an increase of aldosterone during the study. Onreview of the chart, we could find no evidence of volumeloss through bleeding, gastrointestinal, or other sources toexplain a physiologic increase in aldosterone. Furthermore,there was no evidence that the primary disease was affectingadrenal function to explain autonomous mineralocorticoidproduction. The second reason for the observed nonstatisti-cal difference in aldosterone is because our lab is unable toreport plasma aldosterone levels below 69 pmol/L. For thepurpose of the analysis, any value reported as “<69” wasanalyzed as 69 pmol/L. However, clinically significant volumestatus changes occurred through the period of observation,supported by the significant drop in urine osmolality.Although antidiuretic hormone (ADH) was not measured,the urine osmolality provides an indirect measurement that

8 ISRN Oncology

Table 2: Comparative values of TTKG, Na and K balance before and after ondansetron show no effect on renal K wasting.

n Before ondansetron After ondansetron P

PK (mmol/L) 10 3.9 ± 0.3 3.9 ± 0.2 0.774

UK (mmol/L) 10 50.7 ± 22.7 24.7 ± 22.8 0.019

POsm (mmol/kg) 10 287.2 ± 4.2 283.8 ± 18.0 0.573

UOsm (mmol/kg) 10 761.4 ± 183.3 356.7 ± 123.4 0.001

PAld (pmol/L) 10 323.4 ± 484.8 153.9 ± 268.5 0.353

TTKG 5∗ 5.1 ± 1.9 4.7 ± 2.8 0.463

eGFR (ml/min/1.73 m2) 10 148.9 ± 17.9 166.8 ± 46.8 0.207

PNa (mmol/L) 10 138.6 ± 1.8 133.9 ± 18.0 0.426

FENa (%) 10 0.8 ± 0.6 3.1 ± 2.54 0.025

Balance studies

Na intake (mmol) 10 2840.0 ± 2034.1 8032.8 ± 7257.5 0.080

Na output (mmol) 10 50.7 ± 22.7 113.8 ± 41.6 0.002

K intake (mmol) 10 1459.7 ± 1306.1 2274.0 ± 1693.0 0.347

K output (mmol) 10 50.7 ± 22.7 24.8 ± 22.8 0.019

Net Na balance (mmol/kg/hr observation) 10 0.15 ± 0.39 0.06 ± 0.11 0.520

Net K balance (mmol/kg/hr observation) 10 0.11 ± 0.07 0.39 ± 0.82 0.305

Values are presented as mean ± standard deviation.Student’s t-test, paired, two-tailed, significance P < 0.05.Net balance = (intake − output)/weight (kg)/time (hr) of observation period.PK: plasma potassium, mmol/L; UK: urine K, mmol/L; Posm: plasma osmolality, mmol/kg; Pald: plasma aldosterone, pmol/L (lower limit of detection 69pmol/L); TTKG: transtubular potassium gradient; eGFR: estimated glomerular filtration rate (Schwartz [15]); Pna: plasma sodium, mmol/L; FENa: fractionalexcretion of sodium (%).∗5 subjects were not included in this analysis as they developed hypotonic urine relative to blood, invalidating the TTKG assumptions.

suggests ADH activity was abolished after the hydrationphase [13]. This led to the observation that the primaryoutcome measure of TTKG could not be used in half of thestudied patients.

Urinary sodium was noted to increase throughout thestudyand is likely the result of hydration with salt-containingsolutions. This is supported by the sodium balance studiesthat showed significant increases in sodium intake in thelatter half of the study, but no change in the net sodiumbalance. This suggests that the patients were merely excretingwhat they were given as hydration therapy. We also note thatthe urine potassium concentration decreased in our patientsafter ondansetron administration. Interestingly, urine potas-sium concentration decreased by the same factor as the urineosmolality. This is consistent with the balance studies thatshow no effect on overall potassium balance and infer theconcentration change is not due to altered tubular potassiumhandling, but instead decreased tubular water reabsorptionafter adequate hydration.

We previously described a pediatric oncology patientwho reliably developed hypokalemia when exposed toondansetron and reviewed in vitro data that supports amechanism for ondansetron promoting renal potassiumwasting [5]. While we did not observe a similar effect in ourprospective cohort study, we note that there are variablesrelated to the initial patient’s presentation, which mayhave facilitated an ondansetron effect. First, the patient wedescribed had a history of prolonged nausea and poor intake,

which suggests that the patient may have been chronicallynutritionally and total body potassium deplete. In thecurrent study, we excluded patients who had evidence ofprotracted vomiting and poor nutritional intake. The patientwe reported previously showed resistance to potassiumreplacement therapy initially, suggesting that as nutrientswere provided, potassium was shifting intracellularly, poten-tially under the influence of carbohydrate-induced insulingeneration [14]. This may have created an environment thatallowed clinically relevant hypokalemia to develop as therenal potassium wasting documented likely occurred in thesetting of deplete intracellular stores, preventing an extra-cellular shift of potassium and allowing plasma potassiumlevels to fall. All of the patients involved in the study hadreasonable oral potassium intake entering into the study, andthe nutritional records support that oral intake was adequateduring the course of the study. Second, our patient cohortshowed a reduction in urine potassium after ondansetron,which did not affect potassium balance. The trend toward thereduction of aldosterone, albeit not statistically significant,did occur with aggressive hydration. Our initial patient hadadequate hydration and had no detectable aldosterone at thebeginning of our observation, suggesting the baseline stateof potassium secretion in the renal tubule in our cohortwas different. We also note that although not statisticallysignificant, there was a trend to increase potassium intakevia IV administration during the postondansetron phase, as aresult of potassium containing IV solutions administered in

ISRN Oncology 9

greater quantity. This may have prevented the developmentof clinically relevant hypokalemia.

In our study, we allowed the route of administrationof ondansetron to be left to the discretion of the attend-ing physician. Several pharmacokinetic parameters wereconsidered in this discussion [16, 17]. Pharmacokineticdata suggests that oral absorption of ondansetron is 100%,although bioavailability is reduced as low as 50% in thegeneral population due to first pass metabolism in the liver.However, in oncology populations, due to induction of hep-atic metabolism, bioavailability increases to 85%, suggestingthat in the oncology population oral and IV dosing regimensare comparable. Additionally, all ondansetron dosing wason an 8-hour dosing regimen, dosed as needed. The half-life of ondansetron is approximately 3 hours, supporting anobservation period of less than 12 hours to see the effect ofthe drug. Similarly, we did not extend our evaluation beyond12 hours of monitoring as the likelihood of seeing drug effectwould be minimal beyond this time frame.

Our study was constructed to demonstrate whetherondansetron had a durable association with renal K wasting.We do note that out study does have limitations. First, ourstudy is a small cohort and of a short duration. There aremany confounding medications administered in oncologytherapy, and we are unable to determine whether specificdrug combinations in association with ondansetron promoteK wasting in the urine. Similarly, while none of our patientshad preexisting tubular dysfunction, we are unable to deter-mine whether preexisting tubular dysfunction is a require-ment to induce K wasting when dosing ondansetron. How-ever, our population is quite heterogeneous and does demon-strate that within the scope of pediatric oncology practice,clinically significant hypokalemia was not associated withondansetron administration. Secondly, we constructed ourstudy with the intention of applying stringent statisticalparameters, using a power of 90% in the sample sizecalculation, which is more stringent than standard. In deter-mining the sample size to be 7 patients, we recruited 12 inanticipation of patient dropout or the possibility of missingdata. Based on our observations, only five patients were ableto undergo analysis of TTKG. Although this suggests thatthe study is underpowered based on the primary outcome,we also appreciate that had a standard power of 80% beenused, we would have required only 5 patients. However, weacknowledge that the samples size is small and that in anegative study the possibility of failing to detect a significantdifference is a limitation of the study.

We maintain that ondansetron does not appear to beassociated with clinically significant hypokalemia. Althoughwe observed clinically apparent hypokalemia in one patient,when controlling for hydration, adequate nutritional intake,and receiving adequate potassium replacement, our cohortdid not demonstrate a negative potassium balance or thedevelopment of clinically relevant hypokalemia. Consider-ation should be given to ensure maintenance potassiumreplacement is offered during ondansetron administrationfor chemotherapy-induced nausea prophylaxis early in thecourse of treatment, particularly in patients with poorhydration status or poor nutritional status.

Conflict of Interests

The authors declare that they have no conflict of interests.

Acknowledgments

This project was funded through the May McLeod Child-hood Cancer Research Fund, Stollery Children’s Hospitaland the Women’s and Children’s Health Research Institute,Resident Research Award, University of Alberta.

References

[1] M. T. Holdsworth, D. W. Raisch, and J. Frost, “Acute anddelayed nausea and emesis control in pediatric oncologypatients,” Cancer, vol. 106, no. 4, pp. 931–940, 2006.

[2] M. Aapro, “5-HT3-receptor antagonists in the management ofnausea and vomiting in cancer and cancer treatment,” Oncol-ogy, vol. 69, no. 2, pp. 97–109, 2005.

[3] Glaxosmithkline, Prescription medicines: Zofran. Brentford,Middlesex UK: Glaxosmithkline plc, 2010 [updated July,2010, cited October, 2010], http://www.gsk.com/products/prescription-medicines/zofran.htm.

[4] P. Behnam-Motlagh, P. E. Sandstrom, R. Henriksson, and K.Grankvist, “Diverging effects of 5-HT3 receptor antagonistsondansetron and granisetron on estramustine-inhibited cel-lular potassium transport,” Pharmacology and Toxicology, vol.88, no. 5, pp. 244–249, 2001.

[5] S. R. Turner and M. Pinsk, “Ondansetron-associated hypo-kalemia in a 2-year-old with pre-B-cell ALL,” Journal ofPediatric Hematology/Oncology, vol. 30, no. 1, pp. 58–60, 2008.

[6] S. G. Cunningham, “Fluid and electrolyte disturbances asso-ciated with cancer and its treatment,” Nursing Clinics of NorthAmerica, vol. 17, no. 4, pp. 579–593, 1982.

[7] A. Khanna and N. A. Kurtzman, “Metabolic alkalosis,” Journalof Nephrology, vol. 19, no. 9, pp. S86–S96, 2006.

[8] P. Behnam-Motlagh, P. E. Sandstrom, R. Henriksson, andK. Grankvist, “Ondansetron but not granisetron affect cellvolume regulation and potassium ion transport of gliomacells treated with estramustine phosphate,” Journal of CancerResearch and Clinical Oncology, vol. 128, no. 8, pp. 449–455,2002.

[9] Bodyventures, Diet and Fitness today: online health andfitness. Bodyventures, 2010 [updated 2010, cited October,2010], http://www.dietandfitnesstoday.com/.

[10] J. Rodriguez-Soriano, M. Ubetagoyena, and A. Vallo, “Tran-stubular potassium concentration gradient: a useful test toestimate renal aldosterone bio-activity in infants and chil-dren,” Pediatric Nephrology, vol. 4, no. 2, pp. 105–110, 1990.

[11] M. G. Nicholls, “Side effects and metabolic effects ofconverting-enzyme inhibitors,” Clinical and ExperimentalHypertension A, vol. 9, pp. 653–664, 1987.

[12] B. F. Palmer, “A physiologic-based approach to the evaluationof a patient with hypokalemia,” American Journal of KidneyDiseases, vol. 56, no. 6, pp. 1184–1190, 2010.

[13] S. N. Thornton, “Thirst and hydration: physiology and conse-quences of dysfunction,” Physiology and Behavior, vol. 100, no.1, pp. 15–21, 2010.

[14] R. H. Sterns, M. Cox, P. U. Feig, and I. Singer, “Internalpotassium balance and the control of the plasma potassiumconcentration,” Medicine, vol. 60, no. 5, pp. 339–354, 1981.

[15] G. J. Schwartz, L. P. Brion, and A. Spitzer, “The use of plasmacreatinine concentration for estimating glomerular filtration

10 ISRN Oncology

rate in infants, children, and adolescents,” Pediatric Clinics ofNorth America, vol. 34, no. 3, pp. 571–590, 1987.

[16] M. I. Wilde and A. Markham, “Ondansetron: a review of itspharmacology and preliminary clinical findings in novelapplications,” Drugs, vol. 52, no. 5, pp. 773–794, 1996.

[17] F. Roila and A. Del Favero, “Ondansetron clinical pharmacoki-netics,” Clinical Pharmacokinetics, vol. 29, no. 2, pp. 95–109,1995.

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