Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase‐4 inhibitor, in healthy subjects
Authors: Upreti Vijay V. , Boulton David W. , Li Li , Ching Agatha , Su Hong , LaCreta Frank P. , Patel Chirag G. 
Published: February 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin, an anti‐tubercular antibiotic, is a potent inducer of cytochrome P450 (CYP) 3A4 enzymes. Rifampicin is also a potent inducer of some drug efflux transporters and an inhibitor of certain uptake transporter proteins.• Saxagliptin is a potent, selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor, specifically designed for extended inhibition of the DPP‐4 enzyme in the treatment of type 2 diabetes.• Saxagliptin is metabolized by CYP3A4/3A5 to its major metabolite, 5‐hydroxy saxagliptin, which is also a potent inhibitor of DPP‐4.• A drug–drug interaction study of saxagliptin with an archetypal CYP3A4 inducer, rifampicin, provides essential information for clinical use of saxagliptin with respect to the need for dose adjustment when co‐administered with CYP3A4 inducers. WHAT THIS STUDY ADDS • Rifampicin significantly reduced exposure to saxagliptin. There was no decrease in the area under the plasma concentration–time curve and slight increase in the peak plasma concentration for the active metabolite 5‐hydroxy saxagliptin. The saxagliptin total active moieties exposure was slightly lower when co‐administered with rifampicin.• There was no change in the maximum DPP‐4 inhibition and area under the effect−time curve for DPP‐4 inhibition when saxagliptin was co‐administered with rifampicin.• Saxagliptin was generally safe and well tolerated when co‐administered with rifampicin in this study.• The lack of clinically meaningful change of pharmacodynamic effect (plasma DPP‐4 activity) of saxagliptin when co‐administered with rifampicin is consistent with the observed slight reduction in systemic exposure to the total active moieties. Based on these findings, it is not necessary to adjust the saxagliptin dose when co‐administered with rifampicin.AIM To investigate the effect of co‐administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5‐hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5‐hydroxy saxagliptin, its major pharmacologically active metabolite.METHODS In a non‐randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady‐state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5‐hydroxy saxagliptin) and PD (plasma DPP‐4 activity) were measured for up to 24 h on days 1 and 7.RESULTS Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean Cmax and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean Cmax and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5‐hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition−time effect curve over 24 h for DPP‐4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated.CONCLUSIONS Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co‐administered with rifampicin.