Venishetty, Vinay Kumar, Lecot, Jean, Nguyen, Amanda, Prince, William and Zhang, Jie (2024) First-in-human, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Doses Clinical Study to Assess the Safety, Tolerability, and Pharmacokinetics of KAE609 Administered Intravenously in Healthy Adults. Antimicrobial agents and chemotherapy.

Abstract

This first-in-human study assessed the safety, tolerability, and pharmacokinetics (PK) of cipargamin administered intravenously in healthy adults. The study included two parts, Part 1 single ascending dose (SAD: 10.5 mg to 210 mg; n=8 [Active: 6, Placebo: 2] in each cohort) and Part 2 multiple ascending dose (MAD: 60 mg daily and 120 mg daily for 5 days; n=9 [Active: 6, Placebo: 3] in each cohort). The follow-up period after the last dose was on Days 3, 4 and 6 for SAD while it was Days 7, 8 and 10 for MAD. Safety and PK parameters were reviewed at the completion of each cohort prior to the dosing of subsequent cohort. This single and multi-dose study explored its use for clinical development in severe malaria patients.
In the SAD part, an increase in systemic exposure (maximum measured concentration and area under the curve) was observed with increasing dose from 10.5−210 mg post single intravenous dose of cipargamin. Cipargamin was eliminated with a mean T1/2 of 21.9−38.9 hour (h). There was a moderate volume of distribution (92.9−154 L) and low clearance (2.43−4.33 L/h) over the entire dose range.
In the MAD part, the mean accumulation ratio was 1.51 (cipargamin 60 mg) and 2.43 (cipargamin 120 mg) after once-daily administration for 5 days. After Day 5, the mean T1/2 was 35.5 h (cipargamin 60 mg) and 31.9 h (cipargamin 120 mg) with 2-fold increase in dose (60–120 mg) resulting in ~2-fold increased exposure.
Cipargamin was well-tolerated with commonly reported gastrointestinal, neurological, and genitourinary events of mild severity. The incidence of adverse events increased with increasing dose. Higher baseline corrected QTcF (∆QTcF) was seen with increasing exposure after single or multiple IV doses of cipargamin. However, an effect on ΔΔQTcF ≥10 ms can be ruled out at a concentration range studied.
KEYWORDS: Cipargamin, First-in-Human, Intravenous, KAE609, Malaria, Pharmacokinetic, Safety
ClinicalTrials.gov Identifier: NCT04321252

Item Type:	Article
Keywords:	Cipargamin, First-in-Human, Intravenous, KAE609, Malaria, Pharmacokinetic, Safety
Date Deposited:	13 Aug 2024 00:45
Last Modified:	13 Aug 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53546