Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers.
To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.
Li
Susie Xiujiang
SX
Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA.
Pequignot
Edward
E
Panebianco
Deborah
D
Lupinacci
Paul
P
Majumdar
Anup
A
Rosen
Laura
L
Ahmed
Tuli
T
Royalty
Jane E
JE
Rushmore
Thomas H
TH
Murphy
M Gail
MG
Petty
Kevin J
KJ
D000284:Administration, Oral; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000077608:Aprepitant; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011807:Quinolizines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012016:Reference Values; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000932:Antiemetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D009025:Morpholines; D011807:Quinolizines; D012702:Serotonin Antagonists; D000077608:Aprepitant; C060344:dolasetron; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C110718:hydrodolasetron