Modelling the Sitagliptin Effect on Dipeptidyl Peptidase-4 Activity in Adults with Haematological Malignancies After Umbilical Cord Blood Haematopoietic Cell Transplantation

Abstract

Background 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.

Engineering cord blood to improve engraftment after cord blood transplant

“…The median time to neutrophil engraftment was 21 (range, 13-50) days and that of platelet engraftment was 77 (range, 48-220) days, which are not improved over reported results of unmanipulated CBT (77,78).…”

Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26

“…DPP4 does not seem to be as obviously involved with hematopoiesis during nonstressed steady-state conditions, where hematopoiesis seems relatively similar in control mice versus cd26/dpp4 -/-mice or in mice receiving a DPP4 inhibitor such as Diprotin A or sitagliptin. Sitagliptin is currently in clinical trial to accelerate recovery of single CB transplantation for treatment of patients with leukemia and lymphomas [51,52]. DPP4 seems to be mainly active during recovery from radiation or chemotherapy drugs, such as 5-fluorouracil.…”

Ex vivo expansion of hematopoietic stem cells

“…Based on these findings, a clinical trial was conducted to test whether a CD26/DPPIV inhibitor, Sitagliptin, enhanced engraftment after UCB transplant in adult patients with hematological malignancies. Systemic administration of CD26 inhibitor in vivo was safe and may enhance engraftment [171,172].…”