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A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel spiroindolone KAE609, to assess the safety, tolerability and pharmacokinetics in healthy adult volunteers

Leong, Franz Joel Wen and Li, Ruobing and Jain, Jay Prakash and Lefevre, Gilbert and Magnusson, Baldur and Diagana, Thierry Tidiane and Pertel, Peter (2014) A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel spiroindolone KAE609, to assess the safety, tolerability and pharmacokinetics in healthy adult volunteers. Antimicrobial agents and chemotherapy, 58 (10). pp. 6209-6214. ISSN 1098-6596

Abstract

This first in human randomized, double-blind, placebo-controlled, ascending single and multiple oral dose study (KAE609X2101) was designed to evaluate the safety, tolerability and pharmacokinetics of KAE609 in healthy volunteers. It was studied in single dose cohorts (1-300mg, including one 30mg food effect cohort) with 4-10 subjects in each cohort and in multiple dose cohorts (10-150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6-8 days post last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of AUCinf increased in a dose-proportional manner over the dose range of 1-300mg. AUClast and Cmax also increased in an approximately dose-proportional manner. When administered daily for three days, the accumulation ratio on Day 3 (AUC0-24, day3/AUC0-24, day1) was in the range of 1.5-2 in the studied dose range (10-150 mg) and consistent with an elimination half-life of around 24 hours. Urine analysis for unchanged KAE609 revealed negligible amounts (≤ 0.01%) excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC) however Cmax was reduced by around 27%. KAE609 was tolerated within this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/21731

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