Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.
Sitagliptin is a highly selective orally active dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. Ten healthy subjects received single oral doses of 25, 50, 100, 200 and 400 mg final market image tablets in five separate treatment periods in randomized fashion to assess dose proportionality. Blood (up to 72 h post-dose) and urine (up to 24 h post-dose) samples for sitagliptin pharmacokinetic analysis were collected at pre-specified times following administration of sitagliptin. Dose-proportionality of AUC(0-infinity), C(max) and C(24 h) was assessed using a power-law model. The results of this study indicate that plasma AUC(0-infinity) increased in a dose-proportional manner over the 25-400 mg dose range. Over the same dose range, plasma C(max) increased in a greater than dose-proportional manner and C(24 h) increased in a modestly less than dose proportional manner. No clinically meaningful differences in T(max) or apparent t(1/2) were noted across the dose range. Differences in the percentage of the sitagliptin dose excreted unchanged in urine (72.5% pooled across doses) and renal clearance (344 ml/min pooled across doses) were not statistically significant. Sitagliptin was generally well tolerated at all the doses evaluated.
Bergman
Arthur
A
Merck & Co Inc., Whitehouse Station, NJ 07065, USA.
Mistry
Goutam C
GC
Luo
Wen-Lin
WL
Liu
Q
Q
Stone
Julie
J
Wang
Amy
A
Zeng
Wei
W
Chen
Li
L
Dilzer
Stacy
S
Lasseter
Kenneth
K
Herman
Gary A
GA
Wagner
John A
JA
Krishna
Rajesh
R
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000068900:Sitagliptin Phosphate; D013607:Tablets; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011719:Pyrazines; D013607:Tablets; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate