Impact of findings on practice
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Since only limited pharmacogenetic studies on antiemetic drugs in oncology are known, the clinician’s decision regarding antiemetic treatment are currently based on patient’s risk factors and emetogenicity of chemotherapeutic drugs rather than on genetic variants affecting antiemetic drug reponse.
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Genetic variants should only be considered in case of suboptimal antiemetic response in patients treated with highly emetogenic chemotherapy.
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Other investigators may be encouraged to conduct pharmacogenetic studies on antiemetic drug treatment in oncology.
Introduction
Objective
Methods
Result
Drugs target (author, year of publication) | Gene | Endpoint | N | Results |
---|---|---|---|---|
Ondansetron or tropisetron Kaiser et al. (2002), [20] | CYP2D6 | Nausea and vomiting on highly emetogenic cytotoxic drug | 270 | UMs demonstrate the highest incidence and severity of nausea and vomiting. Frequency of UMs was 1.5%. |
Ondansetron or tropisetron Tremblay et al. (2003), [52] | 5-HT3B receptor | Nausea and vomiting on high emetogenic cytotoxic drug | 286 | 5-HT3B receptor gene may serve as genetic predictor for anti-emetic therapy with the _AAG deletion variant (OR = 32) after adjusted with other risk factors of emesis. |
Tropisetron Kaiser et al. (2004), [6] | 5-HT3A receptor | Nausea and vomiting on high emetogenic cytotoxic drug | 242 | There were 21 polymorphisms in 5-HT3A receptor gene, whereas the 15 polymorphisms had partial linkage each of them. The haplotypes in these genes did not have significant association with chemotherapy induced nausea and vomiting. |
Tropisetron, granisetron, ondansetron. Babaoglu et al. (2005), [57] | ABCB 1 (MDR 1) | Nausea and vomiting on high emetogenic cytotoxic drug | 216 | The complete control rate of nausea and vomiting was higher in subjects with ABCB1 TT genotype as compared with those with TC or CC genotype (92.9% vs. 56.1% vs. 47.6%, P = 0.044) |
Ondansetron Fasching et al. (2008), [54] | 5-HT3C receptor | Nausea and vomiting on moderate emetogenic cytotoxic drug | 120 | Variant genotype of K163 N was associated with vomiting (RR = 2.62) |
Dolasetron or tropisetron Ward et al. (2008), [53] | 5-HT3C receptor | Nausea and vomiting on high emetogenic cytotoxic drug | 70 | 5-HT3C receptor gene may not serve as genetic predictor for anti-emetic therapy |
Discussion
Chemotherapy induced nausea and vomiting (CINV)
Emetogenic potential | Cytotoxic drug | Dosage |
---|---|---|
High | Cisplatin | >1,500 mg/m2
|
Cyclophosphamide | ||
Dacarbazine | ||
Mechloretamine | ||
Carmustine | ||
Streptozotocin | ||
Moderate | Cyclophosphamide | <1,500 mg/m2
|
Carboplatin | ||
Doxorubicin | ||
Cytarabine | >1,000 mg/m2
| |
Oxaliplatin | ||
Ifosfamide | ||
Daunorubicin | ||
Epirubicin | ||
Idarubicin | ||
Irinotecan | ||
Low | Paclitaxel | |
Docetaxel | ||
Mitoxantrone | ||
Topotecan | ||
Etoposide | ||
Pemetrexed | ||
Methotrexate | ||
Mitomycin | ||
Gemcitabine | >1,000 mg/m2
| |
Cytarabine | ||
5-Fluorouracil | ||
Bortezomib | ||
Cetuximab | ||
Trastuzumab | ||
Minimal | Bleomycin | |
Busulfan | ||
2-Chlorodeoxyadenosine | ||
Fludarabine | ||
Vinblastine | ||
Vincristine | ||
Vinorelbine | ||
Bevacizumab |
Pharmacology of anti-emetic drugs
5-Hydroxytryptamine 3 receptor antagonists [5-HT3RAs]
Ondansetron | Dolasetron | Granisetron | Tropisetron | Palonosetron | |
---|---|---|---|---|---|
Oral bioavailability | 60–70% | 76% | 60% | 60% | 97% |
Volume of distribution | 1.8 L/kg | 5.8 L/kg | 3.0 L/kg | 5.7–8.6 L/kg | 8.3 L/kg |
Metabolism | CYP1A1a
| CYP2D6 | CYP3A4/5 | CYP2D6 | CYP2D6 |
CYP1A2 | CYP3A/4/5 | CYP1A1 | CYP3A/4/5a
| CYP1A2a
| |
CYP2D6 | CYP3A/4/5a
| ||||
CYP3A/4/5 | |||||
t1/2 elimination in healthy patients (hours) | 3.5–5.5 | 6.9–7.3 | 4.9–7.6 | 5.7 | 24–64.2 |
t1/2 elimination in cancer patients (hours) | 4 | 7.5 | 9–11 | 8 | 128 |