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Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy. | LitMetric

AI Article Synopsis

  • The study developed a PBPK-DO model to predict how saxagliptin and its metabolite M2 behave in the body when taken with CYP3A4 inhibitors or inducers.
  • Using this model, they were able to successfully simulate pharmacokinetic profiles and DPP-4 occupancy of saxagliptin in humans, finding that the predictions matched actual data closely.
  • The results indicated that when saxagliptin is taken with ketoconazole, the dose should be reduced to 2.5 mg, but doses do not need adjustment when taken with delavirdine or rifampicin, despite significant changes in PK profiles.

Article Abstract

We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560969PMC
http://dx.doi.org/10.3389/fphar.2021.746594DOI Listing

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