Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation

Nieves Vélez De Mendizábal, Robert M. Strother, Sherif Farag, Hal Broxmeyer, Steven Messina-Graham, Shripad D. Chitnis, Robert Bies

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)247-259
Number of pages13
JournalClinical Pharmacokinetics
Volume53
Issue number3
DOIs
StatePublished - Mar 2014

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Dipeptidyl Peptidase 4
Cell Transplantation
Hematologic Neoplasms
Fetal Blood
Blood Cells
Appointments and Schedules
Hematopoietic Stem Cells
Pharmacokinetics
Clinical Trials
Dipeptidyl-Peptidase IV Inhibitors
Sitagliptin Phosphate
Type 2 Diabetes Mellitus
Software

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Medicine(all)

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Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation. / Vélez De Mendizábal, Nieves; Strother, Robert M.; Farag, Sherif; Broxmeyer, Hal; Messina-Graham, Steven; Chitnis, Shripad D.; Bies, Robert.

In: Clinical Pharmacokinetics, Vol. 53, No. 3, 03.2014, p. 247-259.

Research output: Contribution to journalArticle

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