Expert Opinion on Drug Metabolism & Toxicology
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Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting M Christofaki & A Papaioannou To cite this article: M Christofaki & A Papaioannou (2014) Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting, Expert Opinion on Drug Metabolism & Toxicology, 10:3, 437-444, DOI: 10.1517/17425255.2014.882317 To link to this article: https://doi.org/10.1517/17425255.2014.882317
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Drug Evaluation
Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting
1.
Introduction to PONV
2.
Pathophysiology of PONV
3.
Introduction to ondansetron
M Christofaki & A Papaioannou†
4.
Pharmacodynamics
University of Crete, Faculty of Medicine, Crete, Greece
5.
Pharmacokinetics and metabolism
6.
Efficacy
7.
Safety profile
8.
Conclusion
9.
Expert opinion
Introduction: Postoperative nausea and vomiting (PONV) is associated with poor patient satisfaction and delayed recovery after general anesthesia. Multiple neurotransmitters are involved in the mediation of PONV but despite the introduction of new antiemetics, no completely effective drug exists for its prevention or treatment. Areas covered: This review provides a detailed description of ondansetron’s chemistry, pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving ondansetron and the management of PONV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). Expert opinion: According to current literature, administering ondansetron 4 mg i.v. near the end of surgery provides sufficient protection against PONV in low- and moderate-risk patients, comparable to traditional antiemetics such as antihistamines and droperidol. High-risk patients require a multimodal approach since one quarter of them will not respond to monotherapy. In the future, transdermal formulation or formulations for nasal or buccal delivery will be available. The development of non-racemic mixture consisting of R-ondansetron would enhance the safety profile and probably the efficacy too. Keywords: 5-HT3 antagonists, ondansetron, pharmacodynamics, pharmacokinetics, postoperative nausea and vomiting Expert Opin. Drug Metab. Toxicol. (2014) 10(3):437-444
1.
Introduction to PONV
Postoperative nausea and vomiting (PONV) is one of the commonest adverse events following surgery under general anesthesia with numerous risk factors [1] affecting 20 -- 30% of general surgical population and 80% of high-risk patients [2,3]. The risk of PONV in adults is estimated with the Apfel simplified score, which includes female gender, history of PONV and/or motion sickness, non-smoking status and postoperative opioid use. The presence of zero, one, two, three or four factors increases the risk to 10, 20, 40, 60 or 80%, respectively [4]. PONV is among the most unpleasant experiences and one of the most common reasons for poor patient satisfaction. Despite the introduction of new antiemetics, no completely effective drug exists for the prevention or treatment of PONV [3,5]. 2.
Pathophysiology of PONV
Structures involved in the pathophysiology of vomiting are disseminated throughout the medulla oblongata [6], suggesting the absence of an anatomical entity as a ‘vomiting center’ [7,8]. The main inputs to the brain stem are from the abdominal 10.1517/17425255.2014.882317 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Mechanism of action Route of administration Chemical structure
Ondansetron hydrochloride Launched Postoperative and chemotherapy induced nausea and vomiting 5-Hydroxytryptamine 3 antagonist Intravenous, intramuscular, orally and per rectum O
CH3 N
N
• HCl • 2H2O
N CH3
Pivotal trial(s)
[46-48]
vagal afferents via the nucleus tractus solitarius [9] and the chemoreceptor trigger zone (CRTZ), a structure outside the blood brain in the area postrema [10]. Enterochromaffin cells in the stomach and intestine release serotonin and play a central role in PONV. Serotonin binds to 5-hydroxytryptamine type 3 (5-HT3) receptors in the gastrointestinal tract stimulating vagal afferents to the CRTZ. The nucleus tractus solitarius receives inputs from the vagus nerve, enterochromaffin and the vestibular and limbic systems. There are least five neurotransmitter systems involved in PONV, including dopaminergic, cholinergic, histaminergic, serotoninergic and neurokinin NK1 systems, rendering the corresponding receptors potential targets for antiemetic drugs [11]. PONV is different from chemotherapy-induced nausea and vomiting (CINV) since the latter mainly involves serotonin release from enteroendocrine cells after stimulation by antineoplastic agents, whereas PONV involves numerous receptors and neurotransmitters [10,12]. 3.
Introduction to ondansetron
Ondansetron hydrochloride dihydrate is a carbazole derivative marketed as a racemic mixture. The empirical formula is C18H19N3O·HCl·2H2O, with a molecular weight of 365.9. It is available for intravenous or intramuscular administration, as tablet, oral solution, orally disintegrating tablet and suppository [13]. It is a weak lipophilic base (pKa = 7.4, logD = 2.28 at pH 7.4) [14] with reduced solubility in aqueous solution [15,16]. The purpose of this report is to review the role of ondansetron for PONV (Box 1). 4.
Pharmacodynamics
Ondansetron acts as a competitive antagonist on 5-HT3 receptor with a binding affinity pKi of 8.07 and can easily be displaced by high concentrations of serotonin [17]. The R- and S-isomers of ondansetron were found equipotent on the rat vagus nerve [18], although the S-isomer had more pronounced effects on animals’ heart [19]. Recent studies reported that R-isomer compared to racemic mixture has a better safety 438
profile and seems to be more effective as antiemetic in humans [20,21]. As it binds to 5-HT1B, 5-HT1C, a1-adrenergic and µ-opioid receptors, it is less selective than other antagonists [22]. The combination of pharmacodynamic and pharmacokinetic data enabled the calculation of 5-HT3 receptors’ occupancy and demonstrated a linear relationship between average receptor occupancy and complete vomiting inhibition in CINV [23]. It was also suggested that interindividual differences in receptor occupancy could explain the differences in the antiemetic efficacy of 5-HT3 antagonists [24]. However, these results were tested only in CINV and not in a real patient population, and therefore, warrant further research. 5.
Pharmacokinetics and metabolism
After a single 8 mg p.o. dose, ondansetron is almost fully and rapidly absorbed. The bioavailability is approximately 60% (50 -- 70%) because of first-pass hepatic metabolism. Bioavailability is slightly higher in women and the elderly, whereas in cancer patients, it is 85 -- 87% because of variations in metabolism [16]. Ondansetron is well absorbed by the colon and rectum. Mean bioavailability of the 24-mg suppository is significantly lower than the 24-mg oral tablet (0.29 ± 0.12 vs 0.65± 0.26). Cmax (34.7 ± 12 vs 94.6 ± 21.9 ng/ml) and Tmax (4.42 ± 1.56 vs 2.33 ± 0.88 h) for suppository and tablet, respectively, differ significantly, suggesting prolonged absorption [25]. The volume of distribution (Vd) of 8 mg ondansetron is approximately 1.9 l/kg and 70 -- 76% is protein-bound. It undergoes extensive hepatic metabolism mainly by hydroxylation and subsequent conjugation. Hepatic elimination is responsible for 95% of ondansetron clearance and < 5% is recovered unchanged in urine. Some of the metabolites are active, but their plasma concentrations are low to contribute to biological activity [26]. Clearance after administration of a single dose 0.15 mg/kg i.v. depends on age, and varies from 0.381 l/h/kg to 0.262 l/h/kg. Elimination half-life (t1/2b) ranges from 3.5 h in adults 19 -- 40 years old to 5.5 h in people > 75 years old [27].
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Pharmacokinetics of ondansetron in children is similar to that in adults [28]. The younger the child, the greater the clearance expressed as per unit body weight. Mean clearance in children 3 -- 7 years old after 2 mg i.v. dose is 0.50 l/kg/h, 20% greater than in children 7 -- 11 years old (0.39 l/kg/h) after 4 mg i.v. dose, which in turn, is 15% faster than in young adults (0.35 l/kg/h). The t1/2b is shorter in the younger compared to the older children (2.6 vs 3.1 h, respectively). The mean weight-normalized Vd is similar to adults. Infants display decreased clearance due to immaturity of the P450 system. In a recent study in oncology and surgical patients aged 1 - 48 months, ondansetron CL was found to be reduced by 31, 53 and 76%, for the 6-, 3- and 1-month-old patient, respectively. In children younger than 6 months, the 0.1 mg/kg dose produced exposure similar to a 0.15 mg/kg dose in older children [29]. Patients with hepatic insufficiency display a higher Vd. Clearance is significantly decreased at a degree analogous to hepatic impairment [30]. The t1/2b varies from 10.05 ± 5.73 h in patients with mild impairment to 19.68 ± 5.96 h in patients with severe insufficiency [30]; therefore, a dose of 8 mg/day should not be exceeded. Renal impairment does not affect ondansetron pharmacokinetics and no adjustment of dosing is needed [31]. The primary metabolic pathway involves CYP3A (CYP3A4, CYP3A5), whereas CYP2D6, CYP1A2 and CYP2E1 constitute the secondary pathway [12]. Subjects with increased CYP2D6 activity are classified as ultrarapid metabolizers and there are studies suggesting increased incidence of ondansetron failure in this population [32,33]. The impact of CYP3A activity on antiemetic efficacy remains questionable [34] and co-medication with enzyme inducers and inhibitors has been discussed as important determinants of CYP3A activity (see section ‘Safety profile’) [34,35]. The metabolism of ondansetron seems to be enantioselective. CYP2D6 activity correlated with concentrations of S-ondansetron, whereas CYP3A5 expressor status mainly influences R-ondansetron. The highest concentrations of S-ondansetron were observed in subjects with no CYP2D6 activity and lowest in those with increased activity [36]. The AUC of R-ondansetron was two times higher in CYP3A5 low expressors compared to high expressors. Interestingly, doubling the dose of ondansetron from 4 to 8 mg significantly increased plasma concentrations only in individuals with low CYP3A, but had no effect in individuals with high enzyme activity, meaning that increasing the dose will not overcome increased activity [36]. The same trend was revealed for CYP2D6 activity without reaching statistical significance. These findings have to be addressed in larger trials. Ondansetron is moderately hydrophobic organic cation, and human organic cation transporter 1 (OCT1) is responsible for its hepatic cellular uptake. In patients with CINV OCT1 genotypes correlated with pharmacokinetics and clinical efficacy of ondansetron; patients lacking fully active OCT1 had higher plasma concentrations and did not vomit at all, whereas patients with one or two fully active
OCT1 alleles had lower plasma concentrations and a mean of 0.75 vomiting episodes/patient was observed in the first 24 h. Plasma concentrations of ondansetron and antiemetic efficacy remained significantly dependent on OCT1 genotypes even after adjustment for the effect of CYP2D6 genotypes. Further systematic research on the interactions between polymorphism affecting cellular uptake and drug metabolism is needed [14]. Current research focuses on the development of formulations for alternative administration routes apart from suppositories, such as transdermal, buccal, sublingual and nasal, in order to bypass first-pass metabolism and provide steady-state plasma concentration and long-term therapy in a single dose. Many studies have been conducted examining the appropriate vehicles and penetration enhancers for transdermal ondansetron. Combinations of isopropanol 15%, l-menthol 1%, N-methyl-2-pyrrolidone 9.5% and water as a solvent resulted in the delivery of the desired ondansetron flux [37,38]. Similarly, high molecular weight chitosan as matrix polymer, 2-(2-ethoxy-ethoxy) ethanol as plasticizer and eucalyptol (1%) as penetration enhancer are found to have good mechanical properties, bioadhesiveness and high permeation enhancer effect [39]. These studies indicate that transdermal ondansetron is feasible and may be available in the future. Formulations for buccal administration are also being developed and tested such as mucoadhesive patches with hydroxyl propyl methyl cellulose [40], chitosan based films and tablets. A study in hamsters examining the pharmacokinetics of buccal chitosan-based formulations compared to oral administration found that buccal administration resulted in similar Cmax and Tmax but t1/2 and AUC0 - 24h were significantly prolonged suggesting enhanced bioavailability and prolonged action [41]. A study in rabbits confirmed improved bioavailability and slower release of the drug from buccal films [42,43]. Regarding nasal administration, animal studies show that this route results in similar to oral Tmax but significantly greater Cmax and AUC0 - 2h [44], while others show significantly prolonged t1/2 and greater AUC0 - ¥ [45]. These results have to be proved in humans. 6.
Efficacy
From the early 1990s, ondansetron was demonstrated as an effective antiemetic for PONV [46-48]. The recommended dose for the prevention of early PONV (0 -- 24 h) is 4 mg i.v. [5]. Trame`r et al. [49] published a systematic review of randomized placebo-controlled trials concerning the efficacy, dose-response and safety of ondansetron. The i.v. dose of ondansetron 4 mg achieved clinically relevant efficacy compared to placebo for early PONV, with a number-neededto-treat (NNT: the number of patients needed to treat to prevent one additional bad outcome) between five and six. However, for late PONV, the 8-mg dose was found to be superior with a decrease in NNT of > 20% [49]. The pediatric dose is 0.05 -- 0.1 mg/kg with a maximum dose of 4 mg i.v. [5].
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Ondansetron prevents vomiting or the need for rescue medication more effectively when administered near the end of surgery, probably because of its short t1/2b [50,51], especially 2 -- 24 h after surgery [52]. After intraoperative administration of ondansetron 4 mg, further administration of ondansetron as rescue treatment in the post-anesthesia care unit (PACU) was no more effective than placebo [53]. A subset of patients may be inherently refractory to 5-HT3 antagonists resulting from genetic polymorphism, or after saturation of serotonin receptors, thus additional antiemetic medication acting on the same receptor may not be effective [53]. Phase II studies There are many studies comparing the relative efficacy of different 5-HT3 antagonists with conflicting results. Most studies do not reveal significant differences between them, apart from longer lasting effects for those with longer t1/2 [54-57]. Dolasetron was found more cost effective because of its lower price and longer lasting effects, eliminating the need for rescue medication [58,59]. Studies comparing ondansetron to palonosetron show conflicting results [60,61]. Studies comparing ondansetron to antihistamines (dimenhydrinate, promethazine, cyclizine) are sparse. In a randomized placebo-controlled trial in 175 patients subjected to day-case gynecological laparoscopy ondansetron 4 mg i.v. was compared to cyclizine 50 mg i.v. [62]. Both drugs significantly reduced nausea compared to placebo, but in the cyclizine group, significantly fewer patients required rescue antiemetic (p = 0.001). Subsequent studies comparing ondansetron to cyclizine [63] or dimenhydrinate [64] failed to reveal significant differences. The combination of ondansetron and cyclizine was found to be more effective compared to ondansetron alone [65]. The efficacy of ondansetron 4 mg vs droperidol 20 mcg/kg was studied in 158 patients who underwent gynecologic laparoscopy [66]. No significant difference regarding PONV or sedation in PACU was observed, but more patients in the ondansetron group reported vomiting on the first postoperative day [66]. A recent multicenter, randomized, double-blind, placebocontrolled study [67] compared ondansetron 4 mg i.v. with casopitant at 0, 50, 100 or 150 mg p.o., or 0 mg ondansetron with casopitant at 150 mg. They studied 702 female patients who underwent laparoscopic cholecystectomy or gynecological surgery. The combination of ondansetron with casopitant at any dose compared to ondansetron alone was significantly better in the prevention of PONV (p = 0.0006) [67]. Unfortunately, the casopitant 150 mg without ondansetron group was enrolled only for safety and not for efficacy analysis [67]. 6.1
Phase III studies Apfel et al. conducted a multicenter randomized study assessing the effectiveness of six interventions for PONV prevention [68]. They studied 5,199 patients at high risk for PONV randomly assigned to receive 1 of 64 possible combinations 6.2
440
of six interventions: ondansetron 4 mg or no ondansetron; dexamethasone 4 mg or no dexamethasone; droperidol 1.25 mg or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. Each antiemetic reduced the incidence of postoperative nausea and vomiting by about 26%. Increasing the number of antiemetics reduced PONV from 52 (no antiemetics), to 37, 28 and 22% when one, two and three antiemetics were administered [68]. In a multicenter, double-blind trial in patients undergoing abdominal surgery, aprepitant was compared to ondansetron in 866 patients randomly assigned to receive aprepitant 40 mg p.o., aprepitant 125 mg or ondansetron 4 mg i.v. preoperatively. Aprepitant at both doses resulted in significantly lower incidence of vomiting during the first 24 and 48 h postoperatively (p < 0.001) [69]. Postmarketing surveillance Ondansetron has been administered to a very large number of patients throughout the world. The only postmarketing surveillance study was conducted in children in 1994 when pediatric use of the drug was off-label [70]. We were unable to find reports of recurring or chronic adverse events associated with ondansetron at doses indicated for PONV. 6.3
7.
Safety profile
The commonest side effects of ondansetron include headache (8 -- 42%), elevation of transaminases (17%), diarrhea (2 -- 5%), xerostomia (5 -- 17%), dizziness (5%) and constipation [71]. Extrapyramidal reactions have been observed at < 1% in adults while two cases were reported in children [72]. Anorexia, changes in blood pressure and heart rate, blurred vision, paresthesia and fever are rare [71,73]. Ondansetron prolongs QTc via blockade of the ether-a-go-go-related gene potassium channel in human myocardium, leading to prolonged repolarization [74]. Although this effect seems dosedependent, significant prolongation of QTc was observed even after a i.v. dose of ondansetron 4 mg [75]. There are case reports of patients with congenital long QT syndrome who developed ventricular tachycardia after an antiemetic ondansetron dose [76]. In 2012, the US FDA released a warning that the 32-mg i.v. dose may affect the electrical activity of the heart, predisposing patients to Torsades de Pointes. The updated label states that ondansetron can be used in adults and children with CINV at a dose of 0.15 mg/kg i.v. every 4 h for three doses; no single intravenous dose should exceed 16 mg. The recommended dose for PONV has not changed. A great concern is raised about co-administration of droperidol and ondansetron since both drugs induce similar QTc prolongation [77]. In a study assessing the effects of co-administration of ondansetron 4 mg with droperidol 1 mg in healthy volunteers, both drugs and their combination prolonged QT. Maximal QTc prolongation was significantly greater in the droperidol and droperidol-ondansetron groups
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compared to ondansetron [75]. QTc remained prolonged for 11 min after ondansetron, 20 min after droperidol and 30 min after the combination [75]. In another study, in patients before induction to anesthesia ondansetron, droperidol or their combination induced modest and transient increase in QTc, similar among groups [78]. Ondansetron should not be used in patients with long QT syndrome, and electrocardiogram (ECG) monitoring is recommended in patients with electrolyte disorders, congestive heart failure, bradyarrhythmias and co-administration with drugs that prolong QT [73]. Its use during pregnancy is of great concern since it crosses the placenta during the first trimester (median fetal/maternal ratio = 0.41) [79]. However, its use is not associated with adverse pregnancy or fetal outcomes [80] or major fetal malformations [81]. An increased risk of cleft palate was observed in a case-control study [82] but further well-controlled studies are warranted. Ondansetron’s interaction with other drugs is low. Rifampicin decreases considerably ondansetron’s plasma concentrations in healthy volunteers, most likely because of induction of CYP3A4 [83]. Co-administration with casopitant, a moderate CYP3A inhibitor, does not affect its pharmacokinetics [84]. Its combination with tramadol has raised concerns regarding reduced analgesic and antiemetic efficacy. Data from recent [85,86] and older studies are controversial [87,88]. Increased nausea and vomiting have also been documented after combination of ondansetron with SSRIs [25]. The co-administration of apomorhine and ondansetron is contraindicated because of reported profound hypotension and loss of consciousness. 8.
Conclusion
Ondansetron is available for oral, parenteral and rectal use, and current research focuses on the development of transdermal, buccal, sublingual and nasal formulations. Optimal intravenous dose is 4 mg administered near the end of surgery. Prophylactic administration leads to complete response in 40 -- 70% of patients. In high-risk patients combination therapy is indicated. Ondansetron has a good safety profile with mild side effects. The most serious is QT prolongation. 9.
Expert opinion
Ondansetron is the first 5-HT3 receptor antagonist used for PONV. It is the drug that newer agents are compared to in studies of non-inferiority. The recommended dose is 4 mg i.v. near the end of surgery and it should be kept in mind that after intraoperative administration of ondansetron, further administration of ondansetron as rescue treatment in PACU is ineffective. On the other hand, the question that needs to be answered is whether supplemental doses of the agent should be administered in outpatients after hospital discharge. Considering that t1/2b of ondansetron is rather short,
3.5 -- 5.5 h, an around-the-clock administration would probably be more rational in high-risk patients. The relative short duration of action of ondansetron questions its effectiveness in the prevention of late or postdischarge nausea and vomiting compared to other agents; in the ambulatory setting, other, longer acting 5-HT3 antagonists may be more appropriate. On the other hand, much research on animals has been done for the development of formulations for alternative administration routes. The findings from animal studies are promising since the buccal, nasal and transdermal administration resulted in enhanced bioavailability and prolonged action. The question that will need to be answered in the future is whether these formulations will be more cost effective compared to the administration of agents with prolonged t1/2b, which are already commercially available. Ondansetron’s effectiveness is affected by genetic polymorphism in the cytochrome P450 but PONV prevention using pharmacogenetic knowledge is still in the early stages. However, data from recent research show that ondansetron’s enantiomers possess different properties. R-ondansetron has better safety profile and seems more effective against PONV as it is not affected by CYP6D polymorphism, whereas S-ondansetron has more pronounced effects on the heart. Further research is needed to confirm these findings and to clarify whether the development of a pure R-ondansetron formulation will lead to a more effective drug with fewer side effects. Ondansetron has been found similarly effective compared to traditional antiemetics; therefore, the choice of an agent over another should be based on cost and side effects. Medical literature is lacking large studies addressing the incidence of adverse effects of the different agents. Sedation, hypotension, dry mouth, dysphoria and restlessness are discussed as the expected effects of droperidol, antihistamines and anticholinergics, but have not been documented as actual effects from the patient’s point of view. Only droperidol has been associated with sedation in the PACU. Therefore, the superiority of ondansetron over traditional antiemetics for the prevention and treatment of PONV has not yet been proved. The administration of a single antiemetic agent decreases the incidence of PONV by 30%, and combination treatment has shown additive effects. Therefore, the best approach for the management of PONV begins during the preoperative evaluation. The risk of PONV should be assessed individually according to Apfel’s criteria. Low-risk patients most probably do not need antiemetics and in moderate-risk patients, administration of a single antiemetic can be sufficient in preventing PONV. As the baseline risk increases, monotherapy may be insufficient. Ondansetron can be administered with dexamethasone. The combination with droperidol is also an option since ondansetron is more effective as an antiemetic and droperidol is more effective against nausea. This latter combination raises concerns regarding prolongation of the QT interval and patients need to be monitored. In patients at high risk for PONV, multiple interventions are needed; however, it should be kept in mind that a reduction of relative
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Affiliation M Christofaki1,2 & A Papaioannou†1,3 MD PhD DEAA † Author for correspondence 1 University Hospital of Heraklion, Department of Anesthesiology, P.O. Box 1352, 71110, Crete, Greece 2 Resident in anesthesiology, University Hospital of Heraklion, Crete, Greece 3 Assistant Professor of Anesthesiology, University of Crete, Faculty of Medicine, Greece Tel: +30 69740 74233, +30 2810 394 733; Fax: +30 2810 394734; E-mail: [email protected]
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Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting M Christofaki & A Papaioannou To cite this article: M Christofaki & A Papaioannou (2014) Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting, Expert Opinion on Drug Metabolism & Toxicology, 10:3, 437-444, DOI: 10.1517/17425255.2014.882317 To link to this article: https://doi.org/10.1517/17425255.2014.882317
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Drug Evaluation
Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting
1.
Introduction to PONV
2.
Pathophysiology of PONV
3.
Introduction to ondansetron
M Christofaki & A Papaioannou†
4.
Pharmacodynamics
University of Crete, Faculty of Medicine, Crete, Greece
5.
Pharmacokinetics and metabolism
6.
Efficacy
7.
Safety profile
8.
Conclusion
9.
Expert opinion
Introduction: Postoperative nausea and vomiting (PONV) is associated with poor patient satisfaction and delayed recovery after general anesthesia. Multiple neurotransmitters are involved in the mediation of PONV but despite the introduction of new antiemetics, no completely effective drug exists for its prevention or treatment. Areas covered: This review provides a detailed description of ondansetron’s chemistry, pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving ondansetron and the management of PONV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). Expert opinion: According to current literature, administering ondansetron 4 mg i.v. near the end of surgery provides sufficient protection against PONV in low- and moderate-risk patients, comparable to traditional antiemetics such as antihistamines and droperidol. High-risk patients require a multimodal approach since one quarter of them will not respond to monotherapy. In the future, transdermal formulation or formulations for nasal or buccal delivery will be available. The development of non-racemic mixture consisting of R-ondansetron would enhance the safety profile and probably the efficacy too. Keywords: 5-HT3 antagonists, ondansetron, pharmacodynamics, pharmacokinetics, postoperative nausea and vomiting Expert Opin. Drug Metab. Toxicol. (2014) 10(3):437-444
1.
Introduction to PONV
Postoperative nausea and vomiting (PONV) is one of the commonest adverse events following surgery under general anesthesia with numerous risk factors [1] affecting 20 -- 30% of general surgical population and 80% of high-risk patients [2,3]. The risk of PONV in adults is estimated with the Apfel simplified score, which includes female gender, history of PONV and/or motion sickness, non-smoking status and postoperative opioid use. The presence of zero, one, two, three or four factors increases the risk to 10, 20, 40, 60 or 80%, respectively [4]. PONV is among the most unpleasant experiences and one of the most common reasons for poor patient satisfaction. Despite the introduction of new antiemetics, no completely effective drug exists for the prevention or treatment of PONV [3,5]. 2.
Pathophysiology of PONV
Structures involved in the pathophysiology of vomiting are disseminated throughout the medulla oblongata [6], suggesting the absence of an anatomical entity as a ‘vomiting center’ [7,8]. The main inputs to the brain stem are from the abdominal 10.1517/17425255.2014.882317 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Mechanism of action Route of administration Chemical structure
Ondansetron hydrochloride Launched Postoperative and chemotherapy induced nausea and vomiting 5-Hydroxytryptamine 3 antagonist Intravenous, intramuscular, orally and per rectum O
CH3 N
N
• HCl • 2H2O
N CH3
Pivotal trial(s)
[46-48]
vagal afferents via the nucleus tractus solitarius [9] and the chemoreceptor trigger zone (CRTZ), a structure outside the blood brain in the area postrema [10]. Enterochromaffin cells in the stomach and intestine release serotonin and play a central role in PONV. Serotonin binds to 5-hydroxytryptamine type 3 (5-HT3) receptors in the gastrointestinal tract stimulating vagal afferents to the CRTZ. The nucleus tractus solitarius receives inputs from the vagus nerve, enterochromaffin and the vestibular and limbic systems. There are least five neurotransmitter systems involved in PONV, including dopaminergic, cholinergic, histaminergic, serotoninergic and neurokinin NK1 systems, rendering the corresponding receptors potential targets for antiemetic drugs [11]. PONV is different from chemotherapy-induced nausea and vomiting (CINV) since the latter mainly involves serotonin release from enteroendocrine cells after stimulation by antineoplastic agents, whereas PONV involves numerous receptors and neurotransmitters [10,12]. 3.
Introduction to ondansetron
Ondansetron hydrochloride dihydrate is a carbazole derivative marketed as a racemic mixture. The empirical formula is C18H19N3O·HCl·2H2O, with a molecular weight of 365.9. It is available for intravenous or intramuscular administration, as tablet, oral solution, orally disintegrating tablet and suppository [13]. It is a weak lipophilic base (pKa = 7.4, logD = 2.28 at pH 7.4) [14] with reduced solubility in aqueous solution [15,16]. The purpose of this report is to review the role of ondansetron for PONV (Box 1). 4.
Pharmacodynamics
Ondansetron acts as a competitive antagonist on 5-HT3 receptor with a binding affinity pKi of 8.07 and can easily be displaced by high concentrations of serotonin [17]. The R- and S-isomers of ondansetron were found equipotent on the rat vagus nerve [18], although the S-isomer had more pronounced effects on animals’ heart [19]. Recent studies reported that R-isomer compared to racemic mixture has a better safety 438
profile and seems to be more effective as antiemetic in humans [20,21]. As it binds to 5-HT1B, 5-HT1C, a1-adrenergic and µ-opioid receptors, it is less selective than other antagonists [22]. The combination of pharmacodynamic and pharmacokinetic data enabled the calculation of 5-HT3 receptors’ occupancy and demonstrated a linear relationship between average receptor occupancy and complete vomiting inhibition in CINV [23]. It was also suggested that interindividual differences in receptor occupancy could explain the differences in the antiemetic efficacy of 5-HT3 antagonists [24]. However, these results were tested only in CINV and not in a real patient population, and therefore, warrant further research. 5.
Pharmacokinetics and metabolism
After a single 8 mg p.o. dose, ondansetron is almost fully and rapidly absorbed. The bioavailability is approximately 60% (50 -- 70%) because of first-pass hepatic metabolism. Bioavailability is slightly higher in women and the elderly, whereas in cancer patients, it is 85 -- 87% because of variations in metabolism [16]. Ondansetron is well absorbed by the colon and rectum. Mean bioavailability of the 24-mg suppository is significantly lower than the 24-mg oral tablet (0.29 ± 0.12 vs 0.65± 0.26). Cmax (34.7 ± 12 vs 94.6 ± 21.9 ng/ml) and Tmax (4.42 ± 1.56 vs 2.33 ± 0.88 h) for suppository and tablet, respectively, differ significantly, suggesting prolonged absorption [25]. The volume of distribution (Vd) of 8 mg ondansetron is approximately 1.9 l/kg and 70 -- 76% is protein-bound. It undergoes extensive hepatic metabolism mainly by hydroxylation and subsequent conjugation. Hepatic elimination is responsible for 95% of ondansetron clearance and < 5% is recovered unchanged in urine. Some of the metabolites are active, but their plasma concentrations are low to contribute to biological activity [26]. Clearance after administration of a single dose 0.15 mg/kg i.v. depends on age, and varies from 0.381 l/h/kg to 0.262 l/h/kg. Elimination half-life (t1/2b) ranges from 3.5 h in adults 19 -- 40 years old to 5.5 h in people > 75 years old [27].
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Ondansetron hydrochloride
Pharmacokinetics of ondansetron in children is similar to that in adults [28]. The younger the child, the greater the clearance expressed as per unit body weight. Mean clearance in children 3 -- 7 years old after 2 mg i.v. dose is 0.50 l/kg/h, 20% greater than in children 7 -- 11 years old (0.39 l/kg/h) after 4 mg i.v. dose, which in turn, is 15% faster than in young adults (0.35 l/kg/h). The t1/2b is shorter in the younger compared to the older children (2.6 vs 3.1 h, respectively). The mean weight-normalized Vd is similar to adults. Infants display decreased clearance due to immaturity of the P450 system. In a recent study in oncology and surgical patients aged 1 - 48 months, ondansetron CL was found to be reduced by 31, 53 and 76%, for the 6-, 3- and 1-month-old patient, respectively. In children younger than 6 months, the 0.1 mg/kg dose produced exposure similar to a 0.15 mg/kg dose in older children [29]. Patients with hepatic insufficiency display a higher Vd. Clearance is significantly decreased at a degree analogous to hepatic impairment [30]. The t1/2b varies from 10.05 ± 5.73 h in patients with mild impairment to 19.68 ± 5.96 h in patients with severe insufficiency [30]; therefore, a dose of 8 mg/day should not be exceeded. Renal impairment does not affect ondansetron pharmacokinetics and no adjustment of dosing is needed [31]. The primary metabolic pathway involves CYP3A (CYP3A4, CYP3A5), whereas CYP2D6, CYP1A2 and CYP2E1 constitute the secondary pathway [12]. Subjects with increased CYP2D6 activity are classified as ultrarapid metabolizers and there are studies suggesting increased incidence of ondansetron failure in this population [32,33]. The impact of CYP3A activity on antiemetic efficacy remains questionable [34] and co-medication with enzyme inducers and inhibitors has been discussed as important determinants of CYP3A activity (see section ‘Safety profile’) [34,35]. The metabolism of ondansetron seems to be enantioselective. CYP2D6 activity correlated with concentrations of S-ondansetron, whereas CYP3A5 expressor status mainly influences R-ondansetron. The highest concentrations of S-ondansetron were observed in subjects with no CYP2D6 activity and lowest in those with increased activity [36]. The AUC of R-ondansetron was two times higher in CYP3A5 low expressors compared to high expressors. Interestingly, doubling the dose of ondansetron from 4 to 8 mg significantly increased plasma concentrations only in individuals with low CYP3A, but had no effect in individuals with high enzyme activity, meaning that increasing the dose will not overcome increased activity [36]. The same trend was revealed for CYP2D6 activity without reaching statistical significance. These findings have to be addressed in larger trials. Ondansetron is moderately hydrophobic organic cation, and human organic cation transporter 1 (OCT1) is responsible for its hepatic cellular uptake. In patients with CINV OCT1 genotypes correlated with pharmacokinetics and clinical efficacy of ondansetron; patients lacking fully active OCT1 had higher plasma concentrations and did not vomit at all, whereas patients with one or two fully active
OCT1 alleles had lower plasma concentrations and a mean of 0.75 vomiting episodes/patient was observed in the first 24 h. Plasma concentrations of ondansetron and antiemetic efficacy remained significantly dependent on OCT1 genotypes even after adjustment for the effect of CYP2D6 genotypes. Further systematic research on the interactions between polymorphism affecting cellular uptake and drug metabolism is needed [14]. Current research focuses on the development of formulations for alternative administration routes apart from suppositories, such as transdermal, buccal, sublingual and nasal, in order to bypass first-pass metabolism and provide steady-state plasma concentration and long-term therapy in a single dose. Many studies have been conducted examining the appropriate vehicles and penetration enhancers for transdermal ondansetron. Combinations of isopropanol 15%, l-menthol 1%, N-methyl-2-pyrrolidone 9.5% and water as a solvent resulted in the delivery of the desired ondansetron flux [37,38]. Similarly, high molecular weight chitosan as matrix polymer, 2-(2-ethoxy-ethoxy) ethanol as plasticizer and eucalyptol (1%) as penetration enhancer are found to have good mechanical properties, bioadhesiveness and high permeation enhancer effect [39]. These studies indicate that transdermal ondansetron is feasible and may be available in the future. Formulations for buccal administration are also being developed and tested such as mucoadhesive patches with hydroxyl propyl methyl cellulose [40], chitosan based films and tablets. A study in hamsters examining the pharmacokinetics of buccal chitosan-based formulations compared to oral administration found that buccal administration resulted in similar Cmax and Tmax but t1/2 and AUC0 - 24h were significantly prolonged suggesting enhanced bioavailability and prolonged action [41]. A study in rabbits confirmed improved bioavailability and slower release of the drug from buccal films [42,43]. Regarding nasal administration, animal studies show that this route results in similar to oral Tmax but significantly greater Cmax and AUC0 - 2h [44], while others show significantly prolonged t1/2 and greater AUC0 - ¥ [45]. These results have to be proved in humans. 6.
Efficacy
From the early 1990s, ondansetron was demonstrated as an effective antiemetic for PONV [46-48]. The recommended dose for the prevention of early PONV (0 -- 24 h) is 4 mg i.v. [5]. Trame`r et al. [49] published a systematic review of randomized placebo-controlled trials concerning the efficacy, dose-response and safety of ondansetron. The i.v. dose of ondansetron 4 mg achieved clinically relevant efficacy compared to placebo for early PONV, with a number-neededto-treat (NNT: the number of patients needed to treat to prevent one additional bad outcome) between five and six. However, for late PONV, the 8-mg dose was found to be superior with a decrease in NNT of > 20% [49]. The pediatric dose is 0.05 -- 0.1 mg/kg with a maximum dose of 4 mg i.v. [5].
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Ondansetron prevents vomiting or the need for rescue medication more effectively when administered near the end of surgery, probably because of its short t1/2b [50,51], especially 2 -- 24 h after surgery [52]. After intraoperative administration of ondansetron 4 mg, further administration of ondansetron as rescue treatment in the post-anesthesia care unit (PACU) was no more effective than placebo [53]. A subset of patients may be inherently refractory to 5-HT3 antagonists resulting from genetic polymorphism, or after saturation of serotonin receptors, thus additional antiemetic medication acting on the same receptor may not be effective [53]. Phase II studies There are many studies comparing the relative efficacy of different 5-HT3 antagonists with conflicting results. Most studies do not reveal significant differences between them, apart from longer lasting effects for those with longer t1/2 [54-57]. Dolasetron was found more cost effective because of its lower price and longer lasting effects, eliminating the need for rescue medication [58,59]. Studies comparing ondansetron to palonosetron show conflicting results [60,61]. Studies comparing ondansetron to antihistamines (dimenhydrinate, promethazine, cyclizine) are sparse. In a randomized placebo-controlled trial in 175 patients subjected to day-case gynecological laparoscopy ondansetron 4 mg i.v. was compared to cyclizine 50 mg i.v. [62]. Both drugs significantly reduced nausea compared to placebo, but in the cyclizine group, significantly fewer patients required rescue antiemetic (p = 0.001). Subsequent studies comparing ondansetron to cyclizine [63] or dimenhydrinate [64] failed to reveal significant differences. The combination of ondansetron and cyclizine was found to be more effective compared to ondansetron alone [65]. The efficacy of ondansetron 4 mg vs droperidol 20 mcg/kg was studied in 158 patients who underwent gynecologic laparoscopy [66]. No significant difference regarding PONV or sedation in PACU was observed, but more patients in the ondansetron group reported vomiting on the first postoperative day [66]. A recent multicenter, randomized, double-blind, placebocontrolled study [67] compared ondansetron 4 mg i.v. with casopitant at 0, 50, 100 or 150 mg p.o., or 0 mg ondansetron with casopitant at 150 mg. They studied 702 female patients who underwent laparoscopic cholecystectomy or gynecological surgery. The combination of ondansetron with casopitant at any dose compared to ondansetron alone was significantly better in the prevention of PONV (p = 0.0006) [67]. Unfortunately, the casopitant 150 mg without ondansetron group was enrolled only for safety and not for efficacy analysis [67]. 6.1
Phase III studies Apfel et al. conducted a multicenter randomized study assessing the effectiveness of six interventions for PONV prevention [68]. They studied 5,199 patients at high risk for PONV randomly assigned to receive 1 of 64 possible combinations 6.2
440
of six interventions: ondansetron 4 mg or no ondansetron; dexamethasone 4 mg or no dexamethasone; droperidol 1.25 mg or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. Each antiemetic reduced the incidence of postoperative nausea and vomiting by about 26%. Increasing the number of antiemetics reduced PONV from 52 (no antiemetics), to 37, 28 and 22% when one, two and three antiemetics were administered [68]. In a multicenter, double-blind trial in patients undergoing abdominal surgery, aprepitant was compared to ondansetron in 866 patients randomly assigned to receive aprepitant 40 mg p.o., aprepitant 125 mg or ondansetron 4 mg i.v. preoperatively. Aprepitant at both doses resulted in significantly lower incidence of vomiting during the first 24 and 48 h postoperatively (p < 0.001) [69]. Postmarketing surveillance Ondansetron has been administered to a very large number of patients throughout the world. The only postmarketing surveillance study was conducted in children in 1994 when pediatric use of the drug was off-label [70]. We were unable to find reports of recurring or chronic adverse events associated with ondansetron at doses indicated for PONV. 6.3
7.
Safety profile
The commonest side effects of ondansetron include headache (8 -- 42%), elevation of transaminases (17%), diarrhea (2 -- 5%), xerostomia (5 -- 17%), dizziness (5%) and constipation [71]. Extrapyramidal reactions have been observed at < 1% in adults while two cases were reported in children [72]. Anorexia, changes in blood pressure and heart rate, blurred vision, paresthesia and fever are rare [71,73]. Ondansetron prolongs QTc via blockade of the ether-a-go-go-related gene potassium channel in human myocardium, leading to prolonged repolarization [74]. Although this effect seems dosedependent, significant prolongation of QTc was observed even after a i.v. dose of ondansetron 4 mg [75]. There are case reports of patients with congenital long QT syndrome who developed ventricular tachycardia after an antiemetic ondansetron dose [76]. In 2012, the US FDA released a warning that the 32-mg i.v. dose may affect the electrical activity of the heart, predisposing patients to Torsades de Pointes. The updated label states that ondansetron can be used in adults and children with CINV at a dose of 0.15 mg/kg i.v. every 4 h for three doses; no single intravenous dose should exceed 16 mg. The recommended dose for PONV has not changed. A great concern is raised about co-administration of droperidol and ondansetron since both drugs induce similar QTc prolongation [77]. In a study assessing the effects of co-administration of ondansetron 4 mg with droperidol 1 mg in healthy volunteers, both drugs and their combination prolonged QT. Maximal QTc prolongation was significantly greater in the droperidol and droperidol-ondansetron groups
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compared to ondansetron [75]. QTc remained prolonged for 11 min after ondansetron, 20 min after droperidol and 30 min after the combination [75]. In another study, in patients before induction to anesthesia ondansetron, droperidol or their combination induced modest and transient increase in QTc, similar among groups [78]. Ondansetron should not be used in patients with long QT syndrome, and electrocardiogram (ECG) monitoring is recommended in patients with electrolyte disorders, congestive heart failure, bradyarrhythmias and co-administration with drugs that prolong QT [73]. Its use during pregnancy is of great concern since it crosses the placenta during the first trimester (median fetal/maternal ratio = 0.41) [79]. However, its use is not associated with adverse pregnancy or fetal outcomes [80] or major fetal malformations [81]. An increased risk of cleft palate was observed in a case-control study [82] but further well-controlled studies are warranted. Ondansetron’s interaction with other drugs is low. Rifampicin decreases considerably ondansetron’s plasma concentrations in healthy volunteers, most likely because of induction of CYP3A4 [83]. Co-administration with casopitant, a moderate CYP3A inhibitor, does not affect its pharmacokinetics [84]. Its combination with tramadol has raised concerns regarding reduced analgesic and antiemetic efficacy. Data from recent [85,86] and older studies are controversial [87,88]. Increased nausea and vomiting have also been documented after combination of ondansetron with SSRIs [25]. The co-administration of apomorhine and ondansetron is contraindicated because of reported profound hypotension and loss of consciousness. 8.
Conclusion
Ondansetron is available for oral, parenteral and rectal use, and current research focuses on the development of transdermal, buccal, sublingual and nasal formulations. Optimal intravenous dose is 4 mg administered near the end of surgery. Prophylactic administration leads to complete response in 40 -- 70% of patients. In high-risk patients combination therapy is indicated. Ondansetron has a good safety profile with mild side effects. The most serious is QT prolongation. 9.
Expert opinion
Ondansetron is the first 5-HT3 receptor antagonist used for PONV. It is the drug that newer agents are compared to in studies of non-inferiority. The recommended dose is 4 mg i.v. near the end of surgery and it should be kept in mind that after intraoperative administration of ondansetron, further administration of ondansetron as rescue treatment in PACU is ineffective. On the other hand, the question that needs to be answered is whether supplemental doses of the agent should be administered in outpatients after hospital discharge. Considering that t1/2b of ondansetron is rather short,
3.5 -- 5.5 h, an around-the-clock administration would probably be more rational in high-risk patients. The relative short duration of action of ondansetron questions its effectiveness in the prevention of late or postdischarge nausea and vomiting compared to other agents; in the ambulatory setting, other, longer acting 5-HT3 antagonists may be more appropriate. On the other hand, much research on animals has been done for the development of formulations for alternative administration routes. The findings from animal studies are promising since the buccal, nasal and transdermal administration resulted in enhanced bioavailability and prolonged action. The question that will need to be answered in the future is whether these formulations will be more cost effective compared to the administration of agents with prolonged t1/2b, which are already commercially available. Ondansetron’s effectiveness is affected by genetic polymorphism in the cytochrome P450 but PONV prevention using pharmacogenetic knowledge is still in the early stages. However, data from recent research show that ondansetron’s enantiomers possess different properties. R-ondansetron has better safety profile and seems more effective against PONV as it is not affected by CYP6D polymorphism, whereas S-ondansetron has more pronounced effects on the heart. Further research is needed to confirm these findings and to clarify whether the development of a pure R-ondansetron formulation will lead to a more effective drug with fewer side effects. Ondansetron has been found similarly effective compared to traditional antiemetics; therefore, the choice of an agent over another should be based on cost and side effects. Medical literature is lacking large studies addressing the incidence of adverse effects of the different agents. Sedation, hypotension, dry mouth, dysphoria and restlessness are discussed as the expected effects of droperidol, antihistamines and anticholinergics, but have not been documented as actual effects from the patient’s point of view. Only droperidol has been associated with sedation in the PACU. Therefore, the superiority of ondansetron over traditional antiemetics for the prevention and treatment of PONV has not yet been proved. The administration of a single antiemetic agent decreases the incidence of PONV by 30%, and combination treatment has shown additive effects. Therefore, the best approach for the management of PONV begins during the preoperative evaluation. The risk of PONV should be assessed individually according to Apfel’s criteria. Low-risk patients most probably do not need antiemetics and in moderate-risk patients, administration of a single antiemetic can be sufficient in preventing PONV. As the baseline risk increases, monotherapy may be insufficient. Ondansetron can be administered with dexamethasone. The combination with droperidol is also an option since ondansetron is more effective as an antiemetic and droperidol is more effective against nausea. This latter combination raises concerns regarding prolongation of the QT interval and patients need to be monitored. In patients at high risk for PONV, multiple interventions are needed; however, it should be kept in mind that a reduction of relative
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Affiliation M Christofaki1,2 & A Papaioannou†1,3 MD PhD DEAA † Author for correspondence 1 University Hospital of Heraklion, Department of Anesthesiology, P.O. Box 1352, 71110, Crete, Greece 2 Resident in anesthesiology, University Hospital of Heraklion, Crete, Greece 3 Assistant Professor of Anesthesiology, University of Crete, Faculty of Medicine, Greece Tel: +30 69740 74233, +30 2810 394 733; Fax: +30 2810 394734; E-mail: [email protected]
