Pharmacokinetics, Safety, and Dialyzability of Gadoquatrane in Patients With Impaired Renal Function: A Comprehensive...

The aims of the study were to evaluate the safety, tolerability and pharmacokinetics of gadoquatrane in men and women with mild to moderate renal impairment and in matching participants with normal renal function, to predict the pharmacokinetics of gadoquatrane in patients with severe renal impairment, and to assess the dialyzability of gadoquatrane. Gadoquatrane is a new gadolinium-based contrast agent (GBCA) currently in clinical development.

This evaluation used data from an open-label, nonrandomized, single-dose study in the following 3 parallel cohorts: (i) participants with mild renal impairment, (ii) participants with moderate renal impairment, and (iii) matching controls with normal renal function (3 × 8 = 24 participants between 51 and 79 years of age; 14 women). Each participant received a single IV bolus injection of gadoquatrane (0.025 mmol/kg body weight, corresponding to 0.1 mmol Gd/kg). Study procedures included safety assessments and collection of plasma and urine samples over 6 months. Gadolinium concentrations in plasma and urine were determined by inductively coupled plasma mass spectrometry. Modeling and simulation were used to predict the exposure in patients with severe renal impairment. In vitro experiments were used to assess the dialyzability of gadoquatrane.

Following IV injection, gadolinium plasma concentrations rapidly declined in all cohorts, albeit at different rates depending on renal function. With increasing degree of renal impairment, the exposure increased and the total as well as the renal clearance decreased. The total body weight-normalized clearance was lower by 21% in participants with mild renal impairment (90% confidence interval: 4; 35%) and by 42% in participants with moderate renal impairment (90% confidence interval: 30; 53%) than in participants with normal renal function. Maximum plasma concentration and volume of distribution were similar in all cohorts. The mean effective plasma half-life, which reflects the overall elimination of gadoquatrane, was short, even in participants with moderate renal impairment (4.1 hours; coefficient of variation: 31.2%). In all cohorts, approximately 90% of the injected dose was recovered in urine within the first 24 hours; after 7 days, recovery was practically complete (92%-97% of the dose administered, on average). Only trace amounts of gadolinium continued to be excreted (median recovery in 24-hour urine in all cohorts at 6 months after the injection: <0.0001% of the dose administered). For patients with severe renal impairment, simulations indicated a continuous decrease in gadoquatrane clearance and increase in exposure with increasing severity of renal impairment. Dialyzability experiments showed that the in vitro kinetic dialysis profile of gadoquatrane is essentially the same as that of gadobutrol.

Gadoquatrane showed the typical, known pharmacokinetic profile of macrocyclic GBCAs. The clearance of gadoquatrane from plasma decreased with increasing degree of renal impairment, but effective elimination of gadoquatrane was also seen in participants with markedly impaired renal function. Trace amounts of gadolinium continued to be excreted until the last observation time point 6 months after the injection, independent of renal function. No relevant safety findings were observed in this study. Because of the safety profile and the pharmacokinetic profile of gadoquatrane correspond to those of the established GBCAs, no dose adjustment is warranted for patients with any degree of renal impairment. The use of modeling and simulation analysis together with in vitro testing for dialyzability made it possible to predict the pharmacokinetics in patients with severe renal impairment or on dialysis and, with that, to avoid exposing vulnerable participants in a clinical trial. EudraCT number: 2018-002426-23.