Nonclinical Safety Assessment of Digadoglucitol, a Novel Magnetic Resonance Imaging Contrast Agent for the Central Nervous System.

OBJECTIVE: Digadoglucitol is a new macrocyclic gadolinium-based contrast agent for magnetic resonance imaging, intended to be used in central nervous system (CNS) and whole body clinical indications. The product features a unique dimeric structure with Gd(III) complexed by 2 macrocyclic chelators, setting it apart from other macrocyclic gadolinium-based contrast agents on the market. The safety profile of digadoglucitol in the context of single diagnostic use in humans was examined using a range of nonclinical studies. MATERIALS AND METHODS: All safety pharmacology and toxicology studies, excluding dose-ranging investigations, were conducted in accordance with Good Laboratory Practice principles. Safety pharmacology evaluations focused on key physiological systems, including the central nervous (in rats), the cardiovascular (assessed in vitro and in monkeys), the respiratory (in rats) systems, and blood compatibility (in vitro). Pharmacokinetic studies were also performed to characterize systemic exposure (in rats); moreover, plasma protein binding, metabolic stability (in vitro), excretion and possible tissue retention of gadolinium (Gd) in rats were evaluated. An extensive toxicological assessment was conducted, including acute toxicity (in rats and mice), extended single-dose and repeated-dose toxicity (in rats and monkeys), as well as reproductive and developmental toxicity (in rats and rabbits), and juvenile toxicity (in rats). Additional studies addressed genotoxic potential (through in vitro assays and in vivo studies in mice), and local tolerance (in rats and monkeys). RESULTS: Digadoglucitol was well tolerated after single or repeated intravenous administrations in rodents and nonrodents. The core battery of safety pharmacology studies showed that digadoglucitol had no adverse effects on the central nervous system and on cardiovascular or respiratory parameters. In vitro, digadoglucitol was found to be compatible with human whole blood and plasma at concentrations up to 0.25 M. The pharmacokinetics of digadoglucitol and the pattern and levels of Gd retention and clearance from brain and body tissues were very similar to those reported for other approved macrocyclic GBCAs widely used for MRI of the central nervous system. At the tested doses, digadoglucitol was rapidly eliminated from the rat plasma and excreted almost exclusively through urine and mainly in the first 8 hours after administration. The extent of plasma protein binding was low in all the tested species (mouse, rat, monkey, and human). Digadoglucitol was shown to be metabolically stable in mouse, rat, monkey, and human liver microsomes. Single-dose and repeated-dose toxicity studies demonstrated no-observed-adverse-effect levels that were, respectively, 10 to 16 times and 5 to 10 times higher than the highest anticipated effective imaging dose in humans (0.1 mmol Gd/kg). Toxicokinetic parameters showed consistent systemic exposures across species. No mutagenic effects were detected in the Ames test, and in the micronucleus test (both in vitro and in vivo). Repeated-dose toxicity studies in rats and monkeys showed no differences in local tolerance at the injection site compared with control. In a preliminary embryo-fetal developmental toxicity study in rats, digadoglucitol administered at 3 mmol Gd/kg/day was associated with slightly reduced mean body weight gain and food consumption, while no effects were observed on embryo-fetal survival or development. Moreover, in a preliminary embryo-fetal developmental toxicity study in rabbits, digadoglucitol had no effects up to the highest tested dose of 3 mmol Gd/kg/day. In a preliminary juvenile toxicity study, digadoglucitol doses up to 3 mmol Gd/kg/day were well tolerated and considered suitable for further studies. CONCLUSIONS: Digadoglucitol showed a favorable nonclinical safety profile, with no adverse effects at exposures well above the anticipated clinical dose. Its pharmacokinetics and Gd‑retention profile were consistent with approved macrocyclic GBCAs. Overall, the data support advancement into clinical development.