Lack of effect of aprepitant on the pharmacokinetics of hydrodolasetron in CYP2D6 extensive and poor metabolizers

Abstract

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.2004.12.073 Geometric Means†‡ Geometric Mean Ratio of DOL With APR/DOL Alone (90 CI)† HDOL Variable (units) CYP2D6 Metabolizer DOL with APR DOL Alone p-Value§ AUC0–∞(ng · hr/mL) Extensive 1132.9 1047.9 1.08 (0.96, 1.22) >0.250 Poor 3223.7 2913.3 1.11 (0.98, 1.25) 0.150 All 1911.1 1747.2 1.09 (1.01, 1.18) 0.065 Extensive 219.9 212.4 1.04 (0.84, 1.27) >0.250 Cmax (ng/mL) Poor 401.1 356.1 1.13 (0.92, 1.38) >0.250 All 297.0 275.1 1.08 (0.94, 1.24) >0.250 Extensive 1.7 2.0 NA NA Tmax (hr) Poor 2.5 2.0 All 2.0 2.0 Extensive 9.0 11.4 t1/2 (hr) Poor 12.1 11.9 All 10.3 11.7