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ANESTHETIC PHARMACOLOGY

Prevention of Postoperative Nausea and Vomiting with Granisetron and Dolasetron in Relation to CYP2D6 Genotype

Department of Anesthesiology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA

	Abstract

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We investigated the efficacy of granisetron and dolasetron in preventing postoperative nausea and vomiting. Because the metabolism of the various antiemetic 5-hydroxytryptamine type 3 (5-HT3) antagonists involves different isoforms of the hepatic cytochrome P450 system, we examined the relationship between the clinical efficacy of these drugs and polymorphic cytochrome P450 2D6 (CYP2D6) genotype. This prospective, randomized, double-blind study involved 150 adult patients with a moderate to high risk for postoperative nausea and vomiting. All subjects received dexamethasone at induction of anesthesia followed by either 12.5 mg of dolasetron or 1 mg of granisetron. We analyzed the number of complete responders (no vomiting or rescue medication) during the first 24 hours after surgery. CYP2D6 genotyping was performed using a TaqMan real-time polymerase chain reaction. A complete response was more frequent in the granisetron group (54.7%) compared with the dolasetron group (38.7%, P < 0.05). In subjects receiving dolasetron, carriers of the duplication of the CYP2D6 allele predicting ultrarapid metabolizer status had more frequent vomiting episodes (P < 0.05) than patients in the granisetron group. It is postulated that the difference in the antiemetic efficacy between two investigated 5-HT3 receptor antagonists may be associated with differences in the carrier status for the duplication of the CYP2D6 allele.

	Introduction

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Several 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are available for the prophylaxis and treatment of postoperative nausea and vomiting (PONV); in general, they are better antiemetics than antinausea drugs. Despite their shared mechanism of action, 5-HT3 receptor antagonists have different chemical structures and exhibit differences in receptor binding affinity, dose response, and duration of effect. Furthermore, although all of the 5-HT3 receptor antagonists are extensively metabolized by cytochrome P450 (CYP), different isoenzymes in this system predominate in the metabolism of each of these drugs (1,2). The highly genetically polymorphic 2D6 isoform of CYP (CYP2D6) is involved in the metabolism of ondansetron, tropisetron, palonosetron, and dolasetron (2). In contrast, the metabolism of granisetron involves the 3A4 isoform of CYP, which, although sensitive to inhibition and induction, has thus far not been associated with significant polymorphism of the CYP3A4 gene in the human population (3). Clinical comparative studies have produced conflicting results of the efficacy of dolasetron and granisetron in preventing chemotherapy-induced nausea and vomiting (CINV) (4–6). In contrast, the results of direct comparison of the therapeutic efficacy of granisetron and dolasetron in prevention of PONV have never been published in the peer-reviewed literature.

The primary objective of this clinical study was to directly compare the therapeutic effectiveness of PONV prophylaxis of two antiemetic 5-HT3 antagonists, dolasetron and granisetron. Secondarily, the study was designed to obtain preliminary data regarding the therapeutic effectiveness of granisetron and dolasetron in carriers of different CYP2D6 genotypes.

	Methods

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The study protocol was approved by the IRB at Hershey Medical Center, and all patients signed a written consent before being enrolled into the study. The study population consisted of adult patients, ASA physical status of I–III, with a moderate to high risk for PONV (Apfel PONV score [7] equal or more than 2). All patients were scheduled for elective surgery under general anesthesia. Exclusion criteria included pregnancy or breast feeding, use of propofol for maintenance of anesthesia, allergy to study medication, neuroaxial anesthesia, history of vomiting within 24 hours before anesthesia, history of cardiac arrhythmia and/or history of antiarrhythmic therapy, and history of vomiting from any organic etiology. All study subjects obtained dexamethasone (IV, 4 mg) before anesthesia induction. Induction of general anesthesia with propofol (2-3 mg/kg) was followed by placement of an endotracheal tube (facilitated with 0.6-0.8 mg/kg rocuronium, IV) or laryngeal mask airway. Maintenance of anesthesia consisted of volatile anesthetic drugs (isoflurane or sevoflurane) and opioid analgesics (combination of fentanyl and morphine). No nitrous oxide was used for maintenance of anesthesia. Neostigmine (2-5 mg) and glycopyrrolate (0.4-0.6 mg), if needed, were used for the reversal of neuromuscular blockade. All patients were expected to be tracheally extubated immediately (within 30 minutes) after surgery. Postoperatively, pain was controlled with IV opioids (e.g., morphine or fentanyl). In all patients, the postdischarge rescue medication consisted of promethazine provided as the regular prescription with recommendation to use it in case of nausea and vomiting (12.5-25 mg, PO, every 4-6 h as needed).

Subjects were randomly allocated to one of two treatment groups according to computer-generated random numbers. Subjects allocated to one group were given dolasetron (12.5 mg IV); patients assigned to the other study group were given granisetron (1 mg IV). Both antiemetic drugs were given 30 min before the end of surgery. All other study personnel and subjects were blinded to treatment assignment.

The blinded investigator made the assessments at 30-min intervals after the end of anesthesia until the time of discharge. Patients were contacted again at 24 h after the operation by an investigator who was unaware of the treatment group. The evaluation of the PONV followed in this study has been previously described in the literature (7,8). Complete response criteria for this study were defined as no vomiting, retching, or dry heaves and no antiemetic rescue therapy at any time starting from emergence from anesthesia through 24 h postoperatively.

An emetic episode was defined as vomiting, retching, or any combination of these events occurring in a rapid sequence (<1 min between events). Nausea verbal rating score was based on numbers 0-10 (0 = no nausea to a maximum of 10 = nausea "as bad as it could be"). In addition, a quality of life assessment was performed that included quality of sleep (characterized as normal, intermittent, or restless), time to resumption of oral fluids (e.g., day of surgery, within 24 hours after surgery, more than 24 hours after surgery), resumption of normal diet (e.g., on day of surgery, within 24 hours after surgery, more than 24 hours after surgery), and degree of satisfaction with control of PONV symptoms (e.g., highly satisfied, somewhat satisfied, dissatisfied, no opinion).

Genotyping analysis was performed simultaneously in all collected samples and analyzed several weeks after enrollment of the last patient in the study. Genomic DNA was isolated from 0.12 mL of whole blood spotted on the IsoCode Cards (Schleicher & Schuell Inc, Keene, NH). DNA was extracted from the card according to the manufacturer recommendations. Each blood sample (0.12 mL) yields approximately 95-180 ng of DNA, which in turn provided enough templates for as many as 10 to 20 amplifications. CYP2D6 genotyping strategy was based on the combined approach of the gene copy number determination by TaqMan real-time polymerase chain reaction (PCR) (9), and subsequent identification of *3, *4, and *6 nonfunctional alleles as well as alleles associated with intermediate metabolizer (IM) phenotype (*9, *10, and *41 alleles) by means of allele-specific 5' nuclease assay, using the pre-developed assay and custom TaqMan® SNP genotyping reagents for allelic discrimination by TaqMan real-time PCR on ABI Prism 7700 Sequence Detection System (Applied Biosystems, Foster City, CA) (10,11). The assay for nonfunctioning alleles *3, *4, and *6, which determine 99% of the poor metabolizer (PM) phenotype in Caucasians, together with CYP2D6 deletion allele *5, was used to predict phenotypic PM. The prediction of IM phenotype was based on the detection of impaired function allele (*41, *9, *10). The alleles *1, *2 and *35 were recognized for the purpose of this study as the equally functioning alleles and called *E allele. With respect to the prediction of the CYP2D6 metabolizer status, the study subjects were divided into four subgroups: PM (one gene copy consisting of deletion allele *5 and nonfunctioning allele or two gene copies consisting of nonfunctioning alleles), IM (presence of at least one decreased but functioning allele with no fully functioning allele), extensive metabolizers (EM; presence of one copy, but not more than two of fully functioning allele), or ultrarapid metabolizers (UM; three or more normally functioning alleles).

Power analysis indicated that 75 patients in each group would be sufficient to demonstrate a clinically significant 25% difference in the incidence of complete response to PONV prophylaxis between two study groups at (type I error probability) of 0.05 and (type II error probability) of 0.2 with the 40% expected rate of complete response. The categorical variables were compared using ² test and Fisher’s exact test, when appropriate. Numerical variables were compared using the nonparametric two-tailed Mann-Whitney U test or parametric two-sided t-test, where applicable. P value of <0.05 was considered statistically significant.

	Results

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A total of 159 subjects signed the informed consent. Nine patients who were enrolled and were not included in the analysis include: three patients who were lost to follow-up for the data collection, one patient enrolled despite the presence of exclusion criteria, one patient withdrawn because of change in anesthetic plan, and four patients withdrawn because of protocol violations in the treatment. The demographic characteristics of the remaining 150 patients are shown in Table 1. There were no statistical differences in any of the demographic characteristics. Likewise, there were no differences between groups in relation to the use and dosage of intraoperative analgesics (e.g., fentanyl, morphine, and ketorolac) or neuromuscular reversal drugs. During the course of the study, no adverse effects were recorded in any of the study subjects.

PONV Efficacy Measurements and Assessment of the Quality of Life
The results of the measurements of the PONV prevention efficacy were evaluated both at the end of the immediate recovery phase (postanesthesia care unit [PACU] discharge) and at the end of the 24-h postoperative period. The analysis at the PACU discharge included the number of complete responders, incidence of vomiting or retching, incidence of nausea, maximum and average nausea scores, and the incidence of the use of antiemetic rescue medication. This analysis did not demonstrate any statistically significant differences between the study groups with respect to any PONV prevention efficacy measurement (Table 2). At the end of the 24-h postoperative period, analysis of the study population revealed (Table 2) a statistically significant more frequent incidence of rescue medication use in the dolasetron group versus the granisetron group and more complete responders in the granisetron group compared with the dolasetron group.

The analysis of the postoperative quality of life is presented in Table 3. We found no statistically significant difference between the study groups with regard to time of first intake of fluids or solids, the level of satisfaction with the prophylactic perioperative antiemetic management, or the quality of the first postoperative night’s sleep.

Table 4 shows the results of CYP2D6 genotyping. In our study population, the genotype predicting PM status was detected in 8 patients (5.3%). The IM status was observed in four patients (2.66%), and EM status was identified by genotyping in 85.3% of the study subjects. More than two copies of CYP2D6 gene were detected in 10 patients (6.6%). All 10 patients with gene duplication carried duplication of fully functioning allele (*E consisting of either *1, *2, or *35), and none had *4 or *41 duplication. There was no significant difference in the frequency of distribution of CYP2D6 metabolizer status between the two study groups.

The distribution pattern of different CYP2D6 metabolizer status identified by genotyping and the absolute number of nausea and vomiting episodes by the study groups are depicted in Table 4. Because of the small number of PM, IM, and UM subjects in both study groups, accurate analysis of the differences in the distribution pattern between responders and nonresponders to PONV prophylaxis could not be statistically assessed. To overcome this limitation, we analyzed the relationship between the CYP2D6 metabolizer status and the absolute number of postoperative vomiting and nausea episodes during the entire 24-h postoperative period in each study group. No statistically significant differences in the incidence of nausea and vomiting were observed in PM, IM, and EM subjects in the two treatment groups (Table 5). However, subjects in the dolasetron group, with the duplication of the CYP2D6 allele and presumed UM status, had significantly more vomiting episodes than patients in the granisetron group (Table 5) during the 24-hour observation period.

	Discussion

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The primary goal of this research was to compare the therapeutic efficacy (measured as the number of complete responders) of granisetron and dolasetron in the prevention of PONV in patients at moderate to high risk for PONV. We found granisetron and dolasetron to be equally effective for preventing PONV in the immediate postoperative period (i.e., until PACU discharge). However, the study drugs showed 16% differences in the frequency of complete response in the postdischarge period over the subsequent 24-h period. The percentage of complete responders was 54.7% during the 24-h postoperative period in the granisetron group compared with 38.7% in the group treated with dolasetron (P = 0.049). This marginal statistical difference was mainly associated with the requirement for rescue medication being significantly reduced in the granisetron group. In this respect, these results are similar to the previously reported superior prophylaxis of CINV for granisetron compared with dolasetron (6). The relatively small difference in the frequency of complete responders was not associated with the statistically significant difference in the quality of life as reported by our subjects during the 24 h after surgery.

There are several possible explanations of the observed differences in the number of complete responders between granisetron and dolasetron. Whereas both antiemetics were administered in the Food and Drug Administration-recommended doses, it has been documented that granisetron can be effectively used for the prophylaxis of PONV at doses as small as 0.1 mg (12). It is therefore possible that the observed differences in the frequency of complete response are associated with the use of nonequipotent pharmacological doses. Furthermore, because the differences were observed after discharge from PACU, the antiemetic properties of granisetron may have been extended for a longer time compared with dolasetron.

The secondary goal of this research was to provide preliminary data about the impact of differences in genetically polymorphic metabolic patterns of the CYP2D6 system and their role and relationship to prevention of PONV using two 5-HT3 antagonists. Available pharmacokinetic data indicate that dolasetron is rapidly (half-life, <1 h) metabolized by carbonyl reductase (13) with subsequent formation of an active metabolite, hydrodolasetron, which is then metabolized, in part, by the CYP2D6 system (plasma half-life, 7-8 h) (14). In contrast, granisetron is almost entirely metabolized (half-life, 5–8 h) by a separate and much less polymorphic CYP3A4 system (3).

The 5-HT3 antagonists are better antiemetics than antinausea drugs, and their rapid metabolism was associated with the decrease in the frequency of vomiting, but not nausea episodes (15). The absolute number of postoperative emetic episodes in our study was larger in the UM subjects in the dolasetron group, but not in the subjects from the granisetron group characterized as UM. These data suggest that the decreased antiemetic efficacy in patients treated with dolasetron may be related in part to the duplication of the CYP2D6 allele. The reduced efficacy of drugs partially metabolized by the CYP2D6 pathway in UM subjects has been well documented for several drugs, namely opioid analgesics (16,17), antipsychotics (18), and antidepressants (10). In addition, published research recognized that ondansetron and tropisetron, two antiemetics used for CINV prevention and both in part metabolized by CYP2D6, were less effective in UM patients compared with other subjects (19). It was also demonstrated in healthy volunteers that carriers of the duplicated CYP2D6 allele showed a decrease in the area under the curve (AUC), smaller maximum plasma concentration, and decreased plasma half-life for tropisetron compared with wild-type allele carriers (20). A more recent study evaluating patients with CYP2D6 allele duplication who received PONV prophylaxis with ondansetron reported a significant increase in the failure of antiemetic treatment compared with patients without CYP2D6 allele duplication, although ondansetron is only partially dependent on the metabolism by the CYP2D6 pathway (21).

The observed difference between the percentages of complete responders in each group (38.7% and 54.7% in the dolasetron and granisetron groups, respectively) and the fact that only 8% and 5.3% of the study subjects in the dolasetron and granisetron groups, respectively, were carriers of the duplicated CYP2D6 allele indicates a potential presence of other mechanisms involved in the nonresponders with two functioning copies of the CYP2D6 allele. One of several explanations may be related to the fact that duplication of the CYP2D6 allele does not accurately predict all cases of the phenotypic UM with considerable overlap in the metabolic capacity of various genotypes. Because genotyping for the duplicated CYP2D6 allele explains only a fraction (10-30%) of the UM phenotype observed in the Caucasian population (22), genotype identification may not confer the necessary phenotypic information, and some subjects with no duplication of the CYP2D6 allele could be phenotypically categorized as UM (23). Based on the data obtained in this and similar studies, only a small percentage of the Caucasian population carries the duplication of the CYP2D6 allele and can be considered at risk for the therapeutic failure when using 5-HT3 antagonists for primary prevention for PONV. Nevertheless, it should be noted that the frequency of the CYP2D6 duplication differs widely among ethnic groups: 7-10% in Spaniards (24), 20% in Saudi Arabians (25), and 29% in Ethiopians (26).

In summary, administration of granisetron, 1 mg IV, and dolasetron, 12.5 mg IV, was equally effective in preventing PONV in the PACU. Administration of granisetron achieved a more frequent complete response rate in the 24-h postdischarge period than administration of dolasetron. No statistically significant differences in the quality of life after surgery and patient satisfaction were observed between the treatment groups. In subjects receiving dolasetron, carriers of the duplication of the CYP2D6 allele predicting UM status had more vomiting episodes than patients in the granisetron group. These preliminary data suggest that the difference in the antiemetic efficacy between the two investigated 5-HT3 receptor antagonists may be associated with the carrier status for the duplication of the CYP2D6 allele.

	Footnotes

 
Accepted for publication December 1, 2005.

Supported by an Independent Investigator Grant for PKJ from Roche Pharmaceuticals.

Address correspondence and reprint requests Piotr K. Janicki, MD, PhD, Department of Anesthesiology, Hershey Medical Center, H 187, 500 University Drive, Hershey, PA 17033-0850. Address e-mail to pjanicki{at}psu.edu.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Janicki, P. K. Articles by Rossi, M. Search for Related Content PubMed PubMed Citation Articles by Janicki, P. K. Articles by Rossi, M., II Related Collections Mechanisms Postanesthetic Care Unit Pharmacology