Abstract
Purpose
To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib.
Methods
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.
Results
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%).
Conclusions
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.
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Puma Biotechnology Inc. funded the provision of editorial support provided by Lee Miller of Miller Medical Communications.
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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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Keyvanjah, K., Cooke, B., Martin, D. et al. Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects. Cancer Chemother Pharmacol 84, 1125–1132 (2019). https://doi.org/10.1007/s00280-019-03951-x
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DOI: https://doi.org/10.1007/s00280-019-03951-x