Lack of Effect of Aprepitant on Hydrodolasetron Pharmacokinetics in CYP2D6 Extensive and Poor Metabolizers

Abstract

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.

Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of a Modified Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan) in Healthy Subjects

“…11,12 Aprepitant also induces CYP2C9 24,26,29 but, unlike rolapitant, does not inhibit CYP2D6. 30 To date, the drug-interaction potential of netupitant is restricted to studies on the CYP3A family, with respect to which netupitant is a moderate inhibitor of CYP3A. 25 IV rolapitant 166.5 mg was well tolerated when coadministered with cocktail probe drugs.…”

“…Nevertheless, both a single dose of IV fosaprepitant and a 3‐day oral aprepitant regimen require a reduction in dexamethasone dose . Aprepitant also induces CYP2C9 but, unlike rolapitant, does not inhibit CYP2D6 . To date, the drug‐interaction potential of netupitant is restricted to studies on the CYP3A family, with respect to which netupitant is a moderate inhibitor of CYP3A …”

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron

“…All adverse events were mild or moderate in intensity, and all events resolved. The ECG effects of hydrodolasetron are dose dependent and were reported to be observed at single doses greater than 200 mg [ 19 ]. Since the recommended oral dose of dolasetron of 100 mg was utilized in the present study, increase in plasma concentration of up to twofold or 100% (equal to a 200-mg dose) can be considered clinically unimportant for the 100-mg dose.…”

“…Similarly, no effect on cardiac function of casopitant coadministered with the serotonin antagonist ondansetron was recently reported [ 15 ]. Further, Li et al [ 19 ] have reported that there is no effect of a similar NK-1 receptor antagonist, aprepitant, on the PK and cardiac safety profile of hydrodolasetron in CYP2D6 EMs or PMs. Consequently, these findings, coupled with no clinically important increase in hydrodolasetron or granisetron exposure in the presence of casopitant, suggest that casopitant is unlikely to increase the potential for either of these drugs to elicit life-threatening arrhythmias.…”

“…Hydrodolasetron is further metabolized by CYP2D6 with minor involvement of CYP3A4 [ 26 ]. Plasma exposures of hydrodolasetron are increased approximately threefold in CYP2D6 poor metabolizers (PMs) as compared to extensive metabolizers (EMs) [ 19 ]. For CYP2D6 PMs, CYP3A4 is likely to play a larger role in the clearance of hydrodolasetron, and these subjects may be more sensitive to coadministration of inhibitors of CYP3A, such as casopitant.…”