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Lack of effect of aprepitant on the pharmacokinetics of hydrodolasetron in CYP2D6 extensive and poor metabolizers
Author(s) -
Li X.,
Pequignot E.,
Panebianco D.,
Majumdar A.,
Selverian D.,
Rosen L.,
Petty K.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.073
Subject(s) - aprepitant , pharmacokinetics , pharmacology , cyp2d6 , active metabolite , vomiting , medicine , antagonist , nausea , oral administration , bioavailability , crossover study , nk1 receptor antagonist , metabolite , receptor antagonist , antiemetic , receptor , metabolism , alternative medicine , cytochrome p450 , pathology , substance p , neuropeptide , placebo
Aprepitant (APR) is the first neurokinin‐1 (NK1) receptor antagonist approved for use with a corticosteroid and a 5‐hydroxytryptamine3 (5HT3) receptor antagonist in the prevention of chemotherapy induced nausea and vomiting (CINV). Dolasetron (DOL) is a 5HT3 antagonist that is converted to the active metabolite hydrodolasetron (HDOL). Metabolism via CYP2D6 contributes significantly to the elimination of HDOL. Because APR may be coadministered with different 5HT3 antagonists including DOL, the purpose of this study was to determine if APR alters the pharmacokinetic profile of HDOL in CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). This was an open‐label, 2‐period, crossover study in which twelve healthy subjects (N=6 EM's and N=6 PM's) received 2 treatments. Treatment A consisted of a single oral dose of 100‐mg DOL. In treatment B, subjects received simultaneously 100‐mg oral DOL and 125‐mg oral APR at 0 hours, followed by single oral doses of 80‐mg APR 24 hours and 48 hours later. The pharmacokinetic data of HDOL are shown in the table below. The data suggest that APR does not affect the pharmacokinetics of HDOL in CYP2D6 extensive or poor metabolizers. Clinical Pharmacology & Therapeutics (2005) 77 , P47–P47; doi: 10.1016/j.clpt.2004.12.073Geometric Means †‡ Geometric Mean Ratio of DOL With APR/DOL Alone (90 CI)†HDOL Variable (units) CYP2D6 Metabolizer DOL with APR DOL Alone p‐Value §AUC 0–∞ (ng · hr/mL) Extensive 1132.9 1047.9 1.08 (0.96, 1.22) >0.250Poor 3223.7 2913.3 1.11 (0.98, 1.25) 0.150All 1911.1 1747.2 1.09 (1.01, 1.18) 0.065Extensive 219.9 212.4 1.04 (0.84, 1.27) >0.250 C max (ng/mL) Poor 401.1 356.1 1.13 (0.92, 1.38) >0.250All 297.0 275.1 1.08 (0.94, 1.24) >0.250Extensive 1.7 2.0 NA NA T max (hr) Poor 2.5 2.0All 2.0 2.0Extensive 9.0 11.4t 1/2 (hr) Poor 12.1 11.9All 10.3 11.7