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11.09.2019 | Original Article

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

verfasst von: Kiana Keyvanjah, Blaire Cooke, David Martin, Daniel Di Primeo, Laura Sterling, Jane Liang, Elizabeth Olek, Igor Rubets, Alvin Wong

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2019

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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 t_max of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CL_ss/F 308.2 and 322.1 L/h; mean V_zτ/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: C_max 61.2 ng/mL and 49.5 ng/mL; AUC_last 1086 ng h/mL and 1153 ng h/mL, and AUC_tau 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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Titel: Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects
verfasst von: Kiana Keyvanjah
Blaire Cooke
David Martin
Daniel Di Primeo
Laura Sterling
Jane Liang
Elizabeth Olek
Igor Rubets
Alvin Wong
Publikationsdatum: 11.09.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03951-x

Springer Medizin

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