Evaluation of the changes in exposure to thiol compounds in chronic kidney disease patients using the PBPK model

Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds. We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active metabolite of prasugrel, R-138727, all of which have a sulfhydryl group, in moderate and severe chronic kidney disease (CKD) patients using a constructed PBPK model. The changes in the exposure to captopril, tiopronin and the active form of dalcetrapib under CKD conditions were well predicted. However, the change in exposure to R-138727, which is a secondary metabolite of prasugrel, was overpredicted. Although these thiol compounds covalently bind to endogenous thiols, our study concluded that changes in exposure to these compounds under CKD conditions can probably be predicted, except for compounds with a complicated mechanism whereby the thiol metabolite is generated.