Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.
BACKGROUND
Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes.


METHODS
Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers.


RESULTS
Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia.


CONCLUSIONS
This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.
Herman
Gary A
GA
Merck & Co., Whitehouse Station, NJ 07065, USA. gary_herman@merck.com
Stevens
Cathy
C
Van Dyck
Kristien
K
Bergman
Arthur
A
Yi
Bingming
B
De Smet
Marina
M
Snyder
Karen
K
Hilliard
Deborah
D
Tanen
Michael
M
Tanaka
Wesley
W
Wang
Amy Q
AQ
Zeng
Wei
W
Musson
Donald
D
Winchell
Gregory
G
Davies
Michael J
MJ
Ramael
Steven
S
Gottesdiener
Keith M
KM
Wagner
John A
JA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D003139:Common Cold / Q000139:chemically induced; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005128:Eye Diseases / Q000139:chemically induced; D005215:Fasting / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D001786:Blood Glucose; D002096:C-Peptide; D004791:Enzyme Inhibitors; D007328:Insulin; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate