Modelling the Sitagliptin Effect on Dipeptidyl Peptidase-4 Activity in Adults with Haematological Malignancies After Umbilical Cord Blood Haematopoietic Cell Transplantation
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Background and Objectives
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.
KeywordsUmbilical Cord Blood Sitagliptin DPP4 Inhibition Antithymocyte Globulin Pharmacodynamic Model
We thank the Disease and Therapeutic Response Modeling Program for the Clinical and Translational Sciences Institute (CTSI) at Indiana University, and David R. Jones for his useful comments on the bioanalytical assays. Analytical work was performed by the Clinical Pharmacology Analytical Core Laboratory, a core laboratory of the Indiana University Melvin and Bren Simon Cancer Center, supported by National Cancer Institute grant no. P30 CA082709.
Conflict of Interest Disclosure Statements
Nieves Vélez de Mendizábal, Shripad Chitnis and Robert Bies were supported by Eli Lilly and Company through the Indiana Clinical and Translational Sciences Institute (CTSI). Steven Messina-Graham was supported as a predoctoral student on under-represented minority grant no. GM079657 and subsequently on grant no. T32 (Hal Broxmeyer) from the US National Institutes of Health (NIH). Robert M. Strother has no conflicts of interest to declare. Hal Broxmeyer is a founder of Cord: Use Family Cord Blood Bank and serves on the medical scientific advisory board of the bank. Parts of these studies were supported by grants from the V Foundation for Cancer Research (Sherif Farag), and Public Service Multi-PI R01HL112669 from the NIH (Hal Broxmeyer and Sherif Farag). Robert Bies is the Director of the Disease and Therapeutic Response Modeling Program, funded through a gift from Eli Lilly & Co. to the Indiana CTSI.
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