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Clinical Pharmacokinetics 2009Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of...
Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6 polymorphisms on the response to other groups of clinically used drugs. Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult to establish clear relationships of their pharmacokinetics and pharmacodynamic parameters to genetic variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be recommended at present. There is initial evidence for a gene-dose effect on commonly used selective serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature. A number of clinical studies have indicated that there are significant relationships between the CYP2D6 genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone and haloperidol. However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dyskinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size, inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice. There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyl-tramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic. Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient. Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response. To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships, further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.
Topics: Analgesics, Opioid; Animals; Antiemetics; Cytochrome P-450 CYP2D6; Genotype; Histamine Antagonists; Humans; Mental Disorders; Muscarinic Antagonists; Phenotype; Polymorphism, Genetic; Psychotropic Drugs; Selective Estrogen Receptor Modulators
PubMed: 19902987
DOI: 10.2165/11318070-000000000-00000 -
Drugs Nov 2009Palonosetron is a second-generation serotonin 5-HT3 receptor antagonist, with a distinct pharmacological profile that differs from first-generation 5-HT3 receptor... (Review)
Review
Palonosetron is a second-generation serotonin 5-HT3 receptor antagonist, with a distinct pharmacological profile that differs from first-generation 5-HT3 receptor antagonists. Intravenous palonosetron is widely indicated for the prevention of chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases following moderately emetogenic chemotherapy (MEC) and the prevention of CINV in the acute phase following highly emetogenic chemotherapy (HEC). In the US, oral palonosetron is approved for the prevention of CINV in the acute phase following MEC (although this formulation is not currently available), and intravenous palonosetron is indicated for the prevention of postoperative nausea and vomiting (PONV) in the first 24 hours following surgery. All indications are currently limited to adult patients. Intravenous palonosetron was noninferior to intravenous ondansetron (with statistically greater efficacy than ondansetron) or dolasetron in preventing CINV following MEC, or to intravenous ondansetron or granisetron in preventing CINV following HEC, in the acute phase. Statistically greater efficacy was seen with intravenous palonosetron than ondansetron or dolasetron in preventing CINV following MEC in the delayed phase. Oral palonosetron was noninferior to intravenous palonosetron in preventing CINV in the acute phase in patients receiving MEC. Intravenous palonosetron was superior to placebo in preventing PONV in the first 24 hours following surgery. Palonosetron was generally well tolerated in clinical trials. Intravenous palonosetron is a valuable option in the prevention of acute- and delayed-phase CINV in adult patients receiving MEC, and of acute-phase CINV in patients receiving HEC. Oral palonosetron is likely to be a useful addition to oral formulations of other 5-HT3 receptor antagonists in preventing CINV in patients receiving MEC. Intravenous palonosetron is a useful alternative to currently recommended agents in PONV prevention.
Topics: Antiemetics; Antineoplastic Agents; Drug Interactions; Humans; Isoquinolines; Nausea; Palonosetron; Postoperative Nausea and Vomiting; Quinuclidines; Serotonin Antagonists; Vomiting
PubMed: 19852528
DOI: 10.2165/11200980-000000000-00000 -
Korean Journal of Anesthesiology Sep 2009Postoperative nausea and vomiting (PONV) is a common problem in patients undergoing thyroidectomy. In this study we evaluated the effects of prophylactic dolasetron...
BACKGROUND
Postoperative nausea and vomiting (PONV) is a common problem in patients undergoing thyroidectomy. In this study we evaluated the effects of prophylactic dolasetron and/or induction with propofol on PONV.
METHODS
Two hundred three patients scheduled thyroidectomy under general anesthesia with sevoflurane were included and were randomly allocated to one of four groups. In control (group C) and dolasetron groups (group D), the patients received thiopental sodium 4-5 mg/kg intravenously for the induction of anesthesia, and the patients in group D received prophylactic intravenous dolasetron 210 microgram/kg. In propofol (group P) and dolasetron + propofol groups (group D + P), the patients received propofol 2 mg/kg intravenously for the induction of anesthesia, and the patients in group D + P received prophylactic intravenous dolasetron 210 microgram/kg. The incidence and severity of PONV, the need for rescue antiemetics, adverse events were assessed during 0 to 1 hour and 1 to 24 hours postoperatively.
RESULTS
During the first 24 hours after anesthesia, the incidences of PONV and postoperative vomiting were significantly reduced in group D + P compared with group C (P < 0.05, respectively). There were no significant differences in postoperative nausea, need for rescue antiemetics, severity of PONV, and adverse events of antiemetics among the four groups.
CONCLUSIONS
In patients with thyroidectomy, combination of prophylactic dolasetron administration and induction with propofol was found to reduce the incidence of PONV during the first 24 hours after anesthesia, compared with that of routine induction with thiopental sodium.
PubMed: 30625880
DOI: 10.4097/kjae.2009.57.3.320 -
Supportive Care in Cancer : Official... Sep 2009The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of...
OBJECTIVE
The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.
MATERIALS AND METHODS
In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.
RESULTS
The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).
CONCLUSION
None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.
Topics: Adolescent; Adult; Antiemetics; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Indoles; Male; Middle Aged; Nausea; Piperazines; Piperidines; Quinolizines; Vomiting; Young Adult
PubMed: 19205754
DOI: 10.1007/s00520-008-0572-4 -
The Lancet. Oncology Feb 2009Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing... (Comparative Study)
Comparative Study Randomized Controlled Trial
Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial.
BACKGROUND
Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy.
METHODS
Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination [AC/EC]) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75 mg), or granisetron (40 microg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0-24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24-120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0.75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00359567.
FINDINGS
1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75.3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73.3%) in the granisetron group (mean difference 2.9% [95% CI -2.70 to 7.27]). During the delayed phase, 315 of 555 patients (56.8%) had complete response in the palonosetron group compared with 249 of 559 patients (44.5%) in the granisetron group (p<0.0001). The main treatment-related adverse events were constipation (97 of 557 patients [17.4%] in the palonosetron group vs 88 of 562 [15.7%] in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 [4.3%] vs 34 of 562 [6.0%]; alanine aminotransferase: 16 of 557 [2.9%] vs 33 of 562 [5.9%]); no grade 4 main treatment-related adverse events were reported.
INTERPRETATION
When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments.
FUNDING
Taiho Pharmaceutical (Tokyo, Japan).
Topics: Adult; Antiemetics; Antineoplastic Agents; Dexamethasone; Double-Blind Method; Female; Granisetron; Humans; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Palonosetron; Quinuclidines; Serotonin Antagonists; Vomiting
PubMed: 19135415
DOI: 10.1016/S1470-2045(08)70313-9 -
Journal of Clinical Anesthesia Sep 2008
Topics: Antiemetics; Humans; Indoles; Quinolizines; Risk Factors; Torsades de Pointes
PubMed: 18929294
DOI: 10.1016/j.jclinane.2008.02.007 -
Emergency Medicine Journal : EMJ Oct 2008
Topics: Antiemetics; Arrhythmias, Cardiac; Drug Overdose; Electrocardiography; Humans; Indoles; Quinolizines; Sodium Bicarbonate; Sodium Channels
PubMed: 18843085
DOI: No ID Found -
Supportive Cancer Therapy Apr 2006Despite significant advances in supportive care in oncology, many patients with cancer still experience chemotherapy- induced nausea and vomiting (CINV). Historically,...
Despite significant advances in supportive care in oncology, many patients with cancer still experience chemotherapy- induced nausea and vomiting (CINV). Historically, there were only 3 neurotransmitter receptors (dopamine D2, cannabinoid- 1, and 5-hydroxytryptamine-3) that were the known targets for antiemetic therapy. Major advances in the management of chemotherapy-induced emesis were seen with the introduction of 5-hydroxytryptamine-3 receptor antagonists, which include palonosetron, ondansetron, tropisetron, dolasetron, and granisetron. However, recently, selective inhibitors of substance P have shown promising activity in the management of CINV in patients with cancer. Substance P mediates a number of biologic effects by binding to a specific neuroreceptor, neurokinin-1 (NK-1). Among the NK-1 receptor antagonists, aprepitant has been approved for the treatment of CINV. Currently, several other NK-1 receptor antagonists, including casopitant, vestipitant, netupitant, and SCH619734, are undergoing clinical evaluation for the prevention of CINV in patients with a variety of malignancies. The clinical potential of these novel NK-1 receptor antagonists and their respective ongoing clinical trials for the management of chemotherapy-induced emesis are discussed briefly herein.
PubMed: 18632487
DOI: 10.3816/SCT.2006.n.011 -
Supportive Cancer Therapy Jan 2005This study assessed the efficacy and safety of dolasetron compared with ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy...
A randomized, multicenter, open-label comparison of the antiemetic efficacy of dolasetron versus ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy.
This study assessed the efficacy and safety of dolasetron compared with ondansetron for the prevention of nausea and vomiting during high-dose myeloablative chemotherapy followed by peripheral blood stem cell support. Twenty centers randomized 197 patients to receive dolasetron 100 mg intravenously (I.V.) followed 8-12 hours later by a single oral dose of dolasetron 100 mg or ondansetron 32 mg I.V., followed 8-12 hours later by a single oral dose of ondansetron 8 mg during high-dose chemotherapy (HDC) regimens for breast cancer (n = 96; 48.7%), non-Hodgkin's lymphoma (n = 83; 42.1%), or Hodgkin's disease (n = 18; 9.1%). All patients received a daily I.V. bolus of dexamethasone 10 mg with study antiemetic agents and a continuous infusion of diphenhydramine, lorazepam, and dexamethasone (ie, BAD pump) throughout the course of the study, with patient-controlled on-demand bolus doses as needed. After completing a daily diary of emetic episodes and rescue medication use, 164 of 197 patients were evaluable. Total plus complete responses (no emesis, no nausea, no rescue) over the entire study period were achieved in 45.7% and 46.9% of patients on the dolasetron and ondansetron arms, respectively. Dolasetron and ondansetron were well-tolerated. This study demonstrates that dolasetron and ondansetron are equally safe and effective in the prevention of nausea and vomiting associated with HDC (P = 0.955).
PubMed: 18628198
DOI: 10.3816/SCT.2005.n.005 -
Tumori 2008
Review
Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Drug Costs; Granisetron; Humans; Indoles; Isoquinolines; Italy; Nausea; Ondansetron; Palonosetron; Primary Prevention; Quinolizines; Quinuclidines; Serotonin Antagonists; Tropisetron; Vomiting
PubMed: 18564623
DOI: No ID Found