Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.
OBJECTIVE
The use of serotonin 5-hydroxytryptamine type 3 receptor antagonists has substantially reduced, but not eliminated, nausea and vomiting in cancer chemotherapy. This study sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on cytochrome P-450 2D6 (CYP2D6) genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated.


METHODS
Included in the study were 270 cancer patients receiving their first day of chemotherapy. Nausea and vomiting were documented using standardized interviews. The intensity of nausea was measured with visual analog scales before and twice during the chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 hours after drug administration was analyzed in a subgroup of 42 patients. CYP2D6 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis.


RESULTS
Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients (P <.03). Approximately 30% of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined ultrarapid meta-bolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 hours (P <.001) and within the period 5 to 24 hours (P <.03) after treatment than all the other patients; the tendency for nausea was similar. This difference was more pronounced in patients treated with tropisetron than in those treated with ondansetron.


CONCLUSIONS
Antiemetic treatment with tropisetron or ondansetron could be improved by adjustment for the CYP2D6 genotype; approximately 50 subjects would have to be genotyped to protect one patient from severe emesis.
Kaiser
Rolf
R
Institute of Clinical Pharmacology and Department of Hematology and Oncology, University Medical Center Charité, Humboldt University of Berlin, Berlin, Germany. rolf.kaiser@med.uni-goettingen.de
Sezer
Orhan
O
Papies
Anja
A
Bauer
Steffen
S
Schelenz
Claudia
C
Tremblay
Pierre-Benoit
PB
Possinger
Kurt
K
Roots
Ivar
I
Brockmöller
Jürgen
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy; D017294:Ondansetron / Q000493:pharmacokinetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077526:Tropisetron; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000970:Antineoplastic Agents; D007211:Indoles; D012702:Serotonin Antagonists; D017294:Ondansetron; D000077526:Tropisetron; D019389:Cytochrome P-450 CYP2D6