Effects of Nacubactam and Its Metabolites on QTc Interval: A Pooled Analysis of Two Randomized Phase 1 Studies.

Nacubactam is a β-lactamase inhibitor. Early-phase studies with 1000/2000/4000/8000 mg nacubactam monotherapy were not powered to assess proarrhythmic risk. Therefore, this analysis pooled electrocardiogram data from two placebo-controlled studies to quantify potential effects of nacubactam on cardiac repolarization. The primary endpoint was ΔQTcF, denoting the time-matched change in QT interval corrected for heart rate. The primary estimand was mean ΔΔQTcF (placebo-corrected ΔQTcF) in healthy adults at double the maximum clinically relevant exposure levels of nacubactam/metabolites. Mixed models for repeated measures and concentration-QTc modeling were used to analyze ΔQTcF. From Mixed models for repeated measures, most 90% confidence intervals for ΔΔQTcF fell below 10 ms, but there were some inconsistencies at 3 h after 1000/2000 mg doses, where 90% confidence intervals straddled 10 ms. However, after 4000/8000 mg doses, 90% confidence intervals fell below 10 ms, with no trend of increasing QTcF prolongation with increasing dose in pooled or individual study data. Moreover, from concentration-QTc modeling, 90% confidence intervals for ΔΔQTcF were below 10 ms for maximum clinically relevant exposure levels, with no evidence of concentration-dependent effects. Results from concentration-QTc modeling fell below the safety margin of 10 ms at relevant analyte levels. While certain confidence intervals from Mixed models for repeated measures straddled 10 ms at 3 h after 1000/2000 mg doses, these inconsistencies were not sustained and not evident at higher doses. Overall, findings support the safety of nacubactam and justify evaluation in larger, multidose, combination-therapy studies and provide regulatory-relevant evidence supporting progression to multidose and combination therapy trials without the need for a dedicated thorough QT study.