In order to investigate the potential for drug-drug interactions (DDI) of AZD3043 with compounds that are substrates for BChE, [14C]AZD3043 was incubated at different time points with remifentanil or succinylcholine, at clinically relevant concentrations, in human liver microsomes and human plasma. The half life (t½) and clearance (CL) for AZD3043 were shown to be unaffected by the co-administration of BChE drugs. It was concluded that there is a low risk for PK interactions in vivo, when administering AZD3043 with other drugs metabolized by BChE, such as remifentanil and succinylcholine. To study the influence of plasma level of BChE on t½ and CL, [14C]AZD3043 was incubated at clinically relevant concentrations at different time points with human plasma from 18 individuals with different BChE phenotypes/BCHE genotypes. The results showed that there was a strong correlation (r2=0.83) between plasma CL, as well as the t½, and different levels of BChE in human plasma.
These in vitro studies demonstrate an appropriate way of supporting the design of in vivo studies. The way forward could be to investigate if there are in vitro–in vivo correlations, with respect to both DDI and activity measurements in subjects with different BChE phenotypes/BCHE genotypes.