title: Pharmacokinetics modeling of exogenous glucagon in type 1 diabetes mellitus patients.
abstract: BACKGROUND
  Insulin-induced hypoglycemia is as a critical barrier in the treatment of type 1 diabetes mellitus patients and may lead to unconsciousness, brain damage, or even death. Clinically, glucagon is used as a rescue drug to treat severe hypoglycemic episodes. More recently, in a bihormonal closed-loop glucose control, glucagon has been used subcutaneously along with insulin for protection against hypoglycemia. In this context, small doses of glucagon are frequently administered. The efficacy and safety of such systems, however, require precise information on the pharmacokinetics of the glucagon transport from the administrative site to the circulation, which is currently lacking. The goal of this work is to address this need by developing and validating a mathematical model of exogenous glucagon transport to the plasma.
  
  
  METHODS
  Eight pharmacokinetic models with various levels of complexity were fitted to nine clinical datasets. An optimal model was chosen in two consecutive steps. At Step 1, all models were screened for parameter identifiability (discarding the unidentifiable candidates). At Step 2, the remaining models are compared based on Bayesian information criterion.
  
  
  RESULTS
  At Step 1, two models were removed for higher parameter fractional SDs. Another three were discarded for location of their optimal parameters on the parameter search boundaries. At Step 2, an optimal model was selected based on the Bayesian information criterion. It has a simple linear structure, assuming that glucagon is injected into one compartment, from where it enters a pool for a slower release into a third, plasma compartment. In the first and third compartments, glucagon is cleared at a rate proportional to its concentration.
  
  
  CONCLUSIONS
  A linear kinetic model of glucagon intervention has been developed and validated. It is expected to provide guidance for glucagon delivery and the construction of preclinical simulation testing platforms.
authors: 1 Department of Psychiatry and Neurobehavioral Sciences, Department of Medicine, University of Virginia , Charlottesville, Virginia.
authors: Dayu
authors: D
authors: Lv
authors: Marc D
authors: MD
authors: Breton
authors: Leon S
authors: LS
authors: Farhy
mesh_terms: D000328:Adult; D000465:Algorithms; D001499:Bayes Theorem; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008991:Monitoring, Physiologic; D019397:Pancreas, Artificial
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D005934:Glucagon
references: Diabetes Care. 2010 Jun;33(6):1282-7
references: 20332355
references: Ann Biomed Eng. 1997 Mar-Apr;25(2):239-51
references: 9084829
references: Proc Natl Acad Sci U S A. 1976 May;73(5):1735-9
references: 1064045
references: Endocrinology. 2012 Mar;153(3):1055-62
references: 22315452
references: J Diabetes Sci Technol. 2010 Nov 01;4(6):1338-44
references: 21129328
references: Sci Transl Med. 2010 Apr 14;2(27):27ra27
references: 20393188
references: Diabetes. 2008 Dec;57(12):3169-76
references: 19033403
references: Am J Physiol. 1979 Jun;236(6):E667-77
references: 443421
references: J Diabetes Sci Technol. 2007 May;1(3):323-30
references: 19885087
references: J Diabetes Sci Technol. 2009 Jan;3(1):44-55
references: 19444330
references: J Diabetes Sci Technol. 2011 Nov 01;5(6):1373-80
references: 22226254
references: CMAJ. 2013 Mar 5;185(4):297-305
references: 23359039
references: Biochemistry. 1969 Jan;8(1):1-7
references: 5777323
references: IEEE Trans Biomed Eng. 2007 Oct;54(10):1740-9
references: 17926672
references: J Clin Endocrinol Metab. 1976 May;42(5):830-8
references: 773949
references: Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S412-23
references: 11460588
references: Am J Physiol Regul Integr Comp Physiol. 2012 Jan 15;302(2):R215-23
references: 22071156
references: Diabetes. 2005 Apr;54(4):1100-7
references: 15793249
references: Biochemistry. 1975 Jun 3;14(11):2536-41
references: 1138871
references: West J Med. 1984 Oct;141(4):467-71
references: 6390972
references: Annu Int Conf IEEE Eng Med Biol Soc. 2008;2008:5445-8
references: 19163949
references: Comput Methods Programs Biomed. 2000 Jul;62(3):249-57
references: 10837910
references: Endocr Pract. 2008 Sep;14(6):750-6
references: 18996798