The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers.
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.
He
Yan-Ling
YL
Exploratory Development, Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139, USA. yanling.he@novartis.com
Sadler
Brian M
BM
Sabo
Ron
R
Balez
Sebastien
S
Wang
Yibin
Y
Campestrini
Joelle
J
Laurent
Aziz
A
Ligueros-Saylan
Monica
M
Howard
Dan
D
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane
Diabetes. 1998 Nov;47(11):1663-70
9792533
J Pharmacokinet Biopharm. 1985 Jun;13(3):289-307
3841365
Diabetologia. 2005 Apr;48(4):616-20
15770466
J Pharmacokinet Biopharm. 1986 Aug;14(4):441-7
3772741
J Clin Pharmacol. 2007 Aug;47(8):998-1004
17660482
Am J Physiol. 1999 Sep;277(3 Pt 2):R910-6
10484511
Diabetes Care. 1992 Feb;15(2):270-6
1547685
Am J Gastroenterol. 1977 Nov;68(5):470-5
607797
Diabetes Care. 1996 Jun;19(6):580-6
8725855
Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E701-7
12773303
Ann Med. 2005;37(5):314-22
16179267
Am J Physiol. 1999 May;276(5 Pt 2):R1541-4
10233049
Lancet. 2002 Mar 9;359(9309):824-30
11897280
Lancet. 1987 Dec 5;2(8571):1300-4
2890903
J Clin Invest. 1993 Jan;91(1):301-7
8423228
Neurogastroenterol Motil. 1995 Dec;7(4):235-8
8574912
Am J Physiol Imaging. 1988;3(4):201-4
3063306
N Engl J Med. 1992 May 14;326(20):1316-22
1348845
Regul Pept. 2005 Jun 15;128(2):159-65
15780435
J Clin Endocrinol Metab. 2005 Aug;90(8):4888-94
15886245
Endocrinology. 2002 Nov;143(11):4397-408
12399437
Dig Dis Sci. 1992 Oct;37(10):1544-7
1396001
Diabetes. 1995 Dec;44(12):1433-7
7589851
J Med Chem. 2003 Jun 19;46(13):2774-89
12801240
J Clin Endocrinol Metab. 2004 May;89(5):2078-84
15126524