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

• Published in: Cancer chemotherapy and pharmacology Vol. 84; no. 5; pp. 1125 - 1132
• Main Authors: Keyvanjah, Kiana, Cooke, Blaire, Martin, David, Di Primeo, Daniel, Sterling, Laura, Liang, Jane, Olek, Elizabeth, Rubets, Igor, Wong, Alvin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2019; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Antidiarrheals - administration & dosage; Antidiarrheals - pharmacology; Area Under Curve; Cancer Research; Constipation; Diarrhea; Drug Administration Schedule; Drug Interactions; Female; Half-Life; Humans; Loperamide - administration & dosage; Loperamide - pharmacology; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Pharmacokinetics; Pharmacology/Toxicology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Safety; Tissue Distribution; Young Adult; Loperamide; Drug interaction; Safety; Pharmacokinetics; Neratinib; Healthy; Volunteers
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-019-03951-x

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.