Vélez de Mendizábal, NievesStrother, Robert M.Farag, Sherif S.Broxmeyer, Hal E.Messina-Graham, StevenChitnis, Shripad D.Bies, Robert R.2016-02-192016-02-192014-03De Mendizábal, N. V., Strother, R. M., Farag, S. S., Broxmeyer, H. E., Messina-Graham, S., Chitnis, S. D., & Bies, R. R. (2014). Modeling Sitagliptin Effect on Dipeptidyl Peptidase 4 (DPP4) Activity in Adults with Hematological Malignancies After Umbilical Cord Blood (UCB) Hematopoietic Cell Transplant (HCT). Clinical Pharmacokinetics, 53(3), 247–259. http://doi.org/10.1007/s40262-013-0109-yhttps://hdl.handle.net/1805/8386Background and Objectives— Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of hematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has shown to be a promising approach in adults with hematological malignancies after umbilical cord blood (UCB) hematopoietic cell transplant (HCT). Based on data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with hematological malignancies after a single-unit UCB HCT. Methods— The clinical study included 24 patients that received myeloablative conditioning followed by 4 oral sitagliptin 600mg with single-unit UCB HCT. Using a nonlinear mixed effects approach, a semi-mechanistic pharmacokinetic/pharmacodynamic model was developed to describe DPP4 activity from this trial data using NONMEM 7.2. The model was used to drive Monte-Carlo simulations to probe various dosage schedules and the attendant DPP4 response. Results— The disposition of sitagliptin in plasma was best described by a 2-compartment model. The relationship between sitagliptin concentration and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice a day or three times a day dosage schedules were superior to once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure. Conclusion— This study provides the first pharmacokinetic/pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, critical for improving time to engraftment in patients after UCB HCT.en-USPublisher PolicyCord Blood Stem Cell TransplantationDipeptidyl Peptidase 4Dipeptidyl-Peptidase IV InhibitorsDose-Response Relationship, DrugHematologic NeoplasmsPyrazinesSitagliptin PhosphateTriazolesArticle