Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects.

Abstract

To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib. This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240mg was administered with loperamide 4mg followed by two further doses of loperamide 2mg 8 and 16h later on Days 1-4. Pharmacokinetic sampling was performed for 72h following each neratinib dose. Safety was monitored throughout the study. A median tmax of ~ 6h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CLss/F 308.2 and 322.1L/h; mean Vzτ/F 7995 and 10,318L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2ng/mL and 49.5ng/mL; AUClast 1086ngh/mL and 1153ngh/mL, and AUCtau 779ngh/mL and 745ngh/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%). Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.