title: In silico design of optimal ratio for co-administration of pramlintide and insulin in type 1 diabetes.
abstract: BACKGROUND
  The ability to simulate in silico experiments is crucial for fast and cost-effective preliminary studies prior to clinical trials. We present an in silico approach to the design of optimal pramlintide-to-insulin (P/I) ratios, using our computer simulator of the human metabolic system, with a population of virtual adult type 1 diabetes mellitus patients and with individual parameters modified to account for the dynamic effects of pramlintide.
  
  
  METHODS
  A model of pramlintide action on gastric emptying was built using data of 15 type 1 diabetes mellitus subjects studied twice with a standardized dual-tracer meal on placebo and pramlintide, which was incorporated in our type 1 diabetes simulator. Extensive in silico experiments on 100 virtual subjects were performed to optimize the co-administration of pramlintide and insulin prior to its submission to clinical trials; several P/I ratios were tested in terms of efficacy, in attenuating postprandial hyperglycemia, and in hypoglycemia safety.
  
  
  RESULTS
  In silico experiments estimated the optimal P/I ratio to be 9 μg of pramlintide per unit (U) of insulin. Additional simulations narrowing the investigated range indicated that P/I ratios of 8 and 10 μg/U would achieve similar performance. Moreover, simulation results suggested that in clinical trials, insulin boluses should be reduced by approximately 21% at a P/I ratio of 9 μg/U to account for the effects of pramlintide and avoid postprandial hypoglycemia.
  
  
  CONCLUSIONS
  We can assert that a valid simulation model of pramlintide action was developed, leading to in silico estimation of optimal pramlintide:insulin co-administration ratio. Clinical trials will confirm (or adjust) this initial estimation.
authors.affiliation: 1 Department of Information Engineering, University of Padova , Padova, Italy .
authors.forename: Francesco
authors.initials: F
authors.lastname: Micheletto
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.forename: Orville
authors.initials: O
authors.lastname: Kolterman
authors.forename: Elaine
authors.initials: E
authors.lastname: Chiquette
authors.forename: Kathrin
authors.initials: K
authors.lastname: Herrmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Schirra
authors.forename: Boris
authors.initials: B
authors.lastname: Kovatchev
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
mesh_terms: D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005260:Female; D005746:Gastric Emptying; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D019518:Postprandial Period; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; C105254:pramlintide