A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects.
A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.
Bloomfield
Daniel M
DM
Merck & Company Inc, Whitehouse Station, New Jersey, USA. daniel_bloomfield@merck.com
Krishna
Rajesh
R
Hreniuk
David
D
Hickey
Lisa
L
Ghosh
Kalyan
K
Bergman
Arthur J
AJ
Miller
Jutta
J
Gutierrez
Maria J
MJ
Stoltz
Randall
R
Gottesdiener
Keith M
KM
Herman
Gary A
GA
Wagner
John A
JA
D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000633:toxicity*; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D012680:Sensitivity and Specificity; D000068900:Sitagliptin Phosphate; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D055815:Young Adult
D001372:Aza Compounds; D054873:Dipeptidyl-Peptidase IV Inhibitors; D024841:Fluoroquinolones; D011719:Pyrazines; D011804:Quinolines; D014230:Triazoles; D000068900:Sitagliptin Phosphate; D000077266:Moxifloxacin