title: The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers.
abstract: OBJECTIVE
  Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers.
  
  
  METHODS
  This was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed.
  
  
  RESULTS
  Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating 'flip-flop' kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h).
  
  
  CONCLUSIONS
  Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.
authors: Exploratory Development, Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139, USA. yanling.he@novartis.com
authors: Yan-Ling
authors: YL
authors: He
authors: Brian M
authors: BM
authors: Sadler
authors: Ron
authors: R
authors: Sabo
authors: Sebastien
authors: S
authors: Balez
authors: Yibin
authors: Y
authors: Wang
authors: Joelle
authors: J
authors: Campestrini
authors: Aziz
authors: A
authors: Laurent
authors: Monica
authors: M
authors: Ligueros-Saylan
authors: Dan
authors: D
authors: Howard
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D015992:Body Mass Index; D001835:Body Weight; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012737:Sex Factors; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane
references: Diabetes. 1998 Nov;47(11):1663-70
references: 9792533
references: J Pharmacokinet Biopharm. 1985 Jun;13(3):289-307
references: 3841365
references: Diabetologia. 2005 Apr;48(4):616-20
references: 15770466
references: J Pharmacokinet Biopharm. 1986 Aug;14(4):441-7
references: 3772741
references: J Clin Pharmacol. 2007 Aug;47(8):998-1004
references: 17660482
references: Am J Physiol. 1999 Sep;277(3 Pt 2):R910-6
references: 10484511
references: Diabetes Care. 1992 Feb;15(2):270-6
references: 1547685
references: Am J Gastroenterol. 1977 Nov;68(5):470-5
references: 607797
references: Diabetes Care. 1996 Jun;19(6):580-6
references: 8725855
references: Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E701-7
references: 12773303
references: Ann Med. 2005;37(5):314-22
references: 16179267
references: Am J Physiol. 1999 May;276(5 Pt 2):R1541-4
references: 10233049
references: Lancet. 2002 Mar 9;359(9309):824-30
references: 11897280
references: Lancet. 1987 Dec 5;2(8571):1300-4
references: 2890903
references: J Clin Invest. 1993 Jan;91(1):301-7
references: 8423228
references: Neurogastroenterol Motil. 1995 Dec;7(4):235-8
references: 8574912
references: Am J Physiol Imaging. 1988;3(4):201-4
references: 3063306
references: N Engl J Med. 1992 May 14;326(20):1316-22
references: 1348845
references: Regul Pept. 2005 Jun 15;128(2):159-65
references: 15780435
references: J Clin Endocrinol Metab. 2005 Aug;90(8):4888-94
references: 15886245
references: Endocrinology. 2002 Nov;143(11):4397-408
references: 12399437
references: Dig Dis Sci. 1992 Oct;37(10):1544-7
references: 1396001
references: Diabetes. 1995 Dec;44(12):1433-7
references: 7589851
references: J Med Chem. 2003 Jun 19;46(13):2774-89
references: 12801240
references: J Clin Endocrinol Metab. 2004 May;89(5):2078-84
references: 15126524