sitagliptin-phosphate and Hematologic-Neoplasms

Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.

Topics: Adult; Cord Blood Stem Cell Transplantation; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Fetal Blood; Hematologic Neoplasms; Humans; Male; Middle Aged; Pilot Projects; Pyrazines; Sitagliptin Phosphate; Transplantation Conditioning; Triazoles; Young Adult

Sitagliptin, an inhibitor of the dipeptidyl peptidase IV (DPP4), has been implicated in the regulation of type 2 diabetes. However, the role and mechanism of sitagliptin administration in total body irradiation (TBI)- induced hematopoietic cells injury are unclear. In this study, we demonstrated that sitagliptin had therapeutic effects on hematopoietic damage, which protected mice from 7.5 Gy TBI-induced death, increased the numbers and colony formation ability of hematopoietic cells. These therapeutic effects might be attributed to the inhibition of NOX4-mediated oxidative stress in hematopoietic cells, and the alleviation of inflammation was also helpful. Therefore, sitagliptin has potential as an effective radiotherapeutic agent for ameliorating TBI-induced hematopoietic injury.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Hematologic Neoplasms; Male; Mice; Sitagliptin Phosphate; Survival Analysis; Whole-Body Irradiation

Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of haematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has been shown to be a promising approach in adults with haematological malignancies after umbilical cord blood (UCB) haematopoietic cell transplantation (HCT). On the basis of data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with haematological malignancies after a single-unit UCB HCT.. The clinical study included 24 patients who received myeloablative conditioning followed by oral sitagliptin with single-unit UCB HCT. Using a nonlinear mixed-effects approach, a semi-mechanistic pharmacokinetic-pharmacodynamic model was developed to describe DPP4 activity from these trial data, using NONMEM version 7.2 software. The model was used to drive Monte Carlo simulations to probe the various dosage schedules and the attendant DPP4 response.. The disposition of sitagliptin in plasma was best described by a two-compartment model. The relationship between sitagliptin concentrations and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice daily or three times daily dosage schedules were superior to a once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure.. 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, which are critical for improving the time to engraftment in patients after UCB HCT.

Topics: Area Under Curve; Cord Blood Stem Cell Transplantation; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Hematologic Neoplasms; Humans; Population; Pyrazines; Sitagliptin Phosphate; Triazoles