LAUSR

The aim of the present study is to develop physiologically based pharmacokinetic (PBPK) models for saxagliptin and its active metabolite, 5-hydroxy saxagliptin, and to predict the effect of co-administration of rifampicin, a strong inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) of saxagliptin and 5-hydroxy saxagliptin in patients with renal impairment. The PBPK models of saxagliptin and 5-hydroxy saxagliptin were developed and validated in GastroPlusTM for healthy adults with or without rifampicin, and adults with varying renal functions. Then, the effect of renal impairment combined with drug-drug interaction (DDI) on saxagliptin and 5-hydroxy saxagliptin PK was investigated. The PBPK models successfully predicted the PK. For saxagliptin, the prediction suggests rifampin greatly weakened the effect of renal impairment on reducing clearance, and the inductive effect of rifampin on parent drug metabolism seems to be increased with an increase in the degree of renal impairment severity. For patients with the same degree of renal impairment, rifampicin would have a slightly synergistic effect on the increase of 5-hydroxy saxagliptin exposure compared with dosed alone. There is an unsignificant decline for the saxagliptin total active moiety exposure values in patients with the same degree of renal impairment. It seems that patients with renal impairment are unlikely to require additional dose adjustments when co-administered with rifampicin, compared with saxagliptin alone. Our study provides a reasonable approach to explore unknown DDI potential in renal impairment. This article is protected by copyright. All rights reserved.