Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects
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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 240 mg daily on Days 1–4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1–4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study.
A median tmax of ~ 6 h 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 322.1 L/h; mean Vzτ/F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2 ng/mL and 49.5 ng/mL; AUClast 1086 ng h/mL and 1153 ng h/mL, and AUCtau 779 ng h/mL and 745 ng h/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.
KeywordsDrug interaction Healthy Volunteers Loperamide Neratinib Pharmacokinetics Safety
Puma Biotechnology Inc. funded the provision of editorial support provided by Lee Miller of Miller Medical Communications.
Compliance with ethical standards
Conflict of interest
At the time the research was conducted, Kiana Keyvanjah, Blaire Cooke, David Martin, Dan DiPrimeo, Jane Liang, Elizabeth Olek, and Alvin Wong were employees/stock holders of the study sponsor (Puma Biotechnology Inc.). Laura Sterling and Igor Rubets have no conflicts of interest to disclose.
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