Nieves Vélez de Mendizábal1,2, Robert M Strother3,4, Sherif S Farag5, Hal E Broxmeyer6, Steven Messina-Graham6, Shripad D Chitnis3,7, Robert R Bies3,7. 1. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street W7138, Indianapolis, IN, 46202, USA. nvelezde@iu.edu. 2. Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, IN, USA. nvelezde@iu.edu. 3. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street W7138, Indianapolis, IN, 46202, USA. 4. Christchurch Hospital, Christchurch, New Zealand. 5. Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. 6. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. 7. Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, IN, USA.
Abstract
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. METHODS: 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. RESULTS: 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. 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, which are critical for improving the time to engraftment in patients after UCB HCT.
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. METHODS: 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. RESULTS: 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. 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, which are critical for improving the time to engraftment in patients after UCB HCT.
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