Safety, Tolerability, and Pharmacokinetics of a Novel Macrocyclic Gadolinium-Based Contrast Agent, HNP-2006, in Healthy Subjects.

Objectives: Gadolinium-based contrast agents (GBCAs) are indispensable in contrast-enhanced magnetic resonance imaging. A higher risk of gadolinium deposition in linear GBCAs required the introduction of macrocyclic GBCAs with a stable molecular structure. We conducted the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics (PKs) of HNP-2006, a novel macrocyclic GBCA, in healthy male subjects.

Materials and methods: A randomized, placebo-controlled, double-blind, single-ascending dose study was conducted. Subjects received either a single intravenous bolus injection of HNP-2006 or its matching placebo with a treatment-to-placebo ratio of 6:2 at the dose level of 0.02, 0.05, 0.1, 0.2, and 0.3 mmol/kg. Safety was assessed through routine clinical assessments. Blood sampling and urine collection were performed up to 72 hours postdose for PK assessments. Noncompartmental methods were used to calculate PK parameters, and a population PK model was constructed.

Results: Overall, 40 subjects completed the study. Fourteen subjects reported 22 treatment-emergent adverse events (TEAEs). The severity of all TEAEs was mild, and the HNP-2006 dose was associated with the incidence of TEAEs. The most common TEAEs included nausea and dizziness, which occurred within an hour of administration. HNP-2006 was rapidly eliminated by urinary excretion with a half-life of 1.8-2.0 hours and showed a dose-proportional PK. A 2-compartment model had the best fit with the population PK analysis.

Conclusions: A single intravenous dose of HNP-2006 was well-tolerated and safe up to 0.30 mmol/kg. HNP-2006 was rapidly excreted in urine and exhibited dose-independent PK profiles.