First-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending doses clinical study to assess the safety, tolerability, and pharmacokinetics of cipargamin administered intravenously in healthy adults.

ABSTRACT

This first-in-human study assessed safety, tolerability, and pharmacokinetics (PK) of cipargamin (intravenous) in healthy adults. It included part 1, single ascending dose [SAD 10.5 mg-210 mg; n = 8 (active 6, placebo 2)], and part 2, multiple ascending dose [MAD 60 and 120 mg daily for 5 days; n = 9 (active 6, placebo 3)]. Last dose follow-ups were on days 3, 4, and 6 for SAD and 7, 8, and 10 for MAD. Safety and PK review was done at completion of each cohort. We explored the cipargamin use for clinical development in patients with severe malaria. In SAD part, systemic exposure (maximum measured concentration and area under the curve) increased with increasing dose (10.5 mg-210 mg) following single intravenous dose. Cipargamin was eliminated with a mean T1/2 of 21.9-38.9 h. Volume of distribution (92.9 L-154 L) and clearance (2.43 L/h-4.33 L/h) was moderate and low, respectively, across the dose range. In MAD part, the mean accumulation ratio was 1.51 (60 mg) and 2.43 (120 mg) after once-daily cipargamin administration for 5 days. After day 5, the mean T1/2 was 35.5 (60 mg) and 31.9 h (120 mg) with twofold dose increase (60-120 mg) resulting in ~2-fold increased exposure. Cipargamin was well tolerated with commonly reported mild gastrointestinal, neurological, and genitourinary events. Increasing exposure to cipargamin showed higher baseline-corrected QTcF, and model-predicted ΔΔQTcF indicated that an effect on ΔΔQTcF ≥10 ms can be excluded up to 6470 ng/mL. However, these results should be interpreted with caution due to inadequate Fridericia's QT correction. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04321252.