Leong, Franz Joel Wen, Zhao, Rong, Zeng, Shuqi, Magnusson, Baldur, 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 imidazolopiperazine KAF156, to assess safety, tolerability and pharmacokinetics in healthy adult volunteers. Antimicrobial agents and chemotherapy, 58 (11). pp. 6437-6443. ISSN 1098-6596

Abstract

KAF156 belongs to a new class of antimalarial, imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single and multiple ascending dose study in 70 healthy volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults, and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single dose cohorts (10-1200 mg, including one 400 mg food effect cohort; (4-10 subjects/cohort); and in multiple dose cohorts (60-600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6-14 days post last dose.
KAF156 was well tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (N=4, 11.1%), diarrhea (N=3, 8.3%), dizziness (N=3, 8.3%) and abdominal pain (N=2, 5.6%) were the commonest adverse events. Headache (N=4, 16.7%), nausea (N=3, 12.5%), upper respiratory tract infection (N=3, 12.5%), and dizziness (N=2, 8.3%) were the commonest adverse events following multiple doses.
KAF156 Tmax was between 1.0-6.0 hours. Both AUC and Cmax increased more than dose-proportionally in both single and multiple ascending dose cohorts. The terminal half-life was 42.5-70.7 hours. There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean Cmax decreased from 778 ng/mL to 627 ng/mL and Tmax was delayed to a median of 3.0-6.0 h under fed conditions. Renal elimination is a minor route for KAF156.

Item Type:	Article
Keywords:	KAF156, malaria, first-in-human, safety, pharmacokinetics, imidazolopiperazine
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/22266