Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 4; pp. 721 - 727
• Main Authors: Liu, Dongyang, Jiang, Ji, Zhang, Li, Tan, Fenlai, Wang, Yingxiang, Zhang, Don, Hu, Pei
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2014; Springer; Springer Nature B.V
• Subjects: Adult; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Cancer Research; Cross-Over Studies; Crown Ethers - administration & dosage; Crown Ethers - adverse effects; Crown Ethers - blood; Crown Ethers - pharmacokinetics; Dose-Response Relationship, Drug; Food-Drug Interactions; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - blood; Quinazolines - pharmacokinetics; Xenograft Model Antitumor Assays; Young Adult; Icotinib; Healthy subjects; Pharmacokinetics; Tyrosine kinase inhibitor; EGFR; Antineoplastic agent; Human; Drug; Evaluation; Healthy subject; Enzyme; Toxicity; Transferases; Enzyme inhibitor; Epidermal growth factor receptor; Dose; Protein-tyrosine kinase; Food
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2398-8

Purpose Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. Methods Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study ( n  = 12) and a randomized two-way crossover food-effect study ( n  = 10). Results Plasma concentration of Icotinib reached peak at a median T max of 0.75–3.5 h after single dose and then declined with a mean t 1/2β of 6.02–7.83 h. Over the dose range of 100–600 mg, AUC values were proportional to dose and C max showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean C max and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported. Conclusion The current work demonstrated that Icotinib was well tolerated in healthy male subjects ( n  = 22) over the dose range of 100–600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.