Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients.
OBJECTIVE
Dutogliptin is a novel, orally available, potent, and selective DPP4 inhibitor that improves glycemic control in type 2 diabetic patients. The objective of this study was to evaluate the potential pharmacokinetic and pharmacodynamic interactions, as well as the tolerability, of dutogliptin and metformin alone and in combination in type 2 diabetic patients.


METHODS
This was a single-center, randomized, open-label, 3-way, crossover study in type 2 diabetic patients. All patients received three treatment regimens, each of 5 days duration in order to reach steady state: 400 mg once daily of dutogliptin (the anticipated clinical dose); 1000 mg metformin twice daily (maximum effective clinical dose); and concomitant administration of 400 mg dutogliptin once daily and 1000 mg metformin twice daily.


RESULTS
Co-administration of dutogliptin and metformin did not alter the pharmacokinetics of either agent. The geometric mean ratio, GMR (dutogliptin + metformin/dutogliptin) of the area under the plasma concentration-time curve (AUC(0-24h)) at steady state was 0.91 (90% CI: 0.79-1.06; p = 0.29); the GMR of the maximum plasma concentrations (C(max)) was 0.95 (90% CI: 0.76-1.19; p = 0.70); the time to maximum plasma concentrations (T(max)) was essentially the same for dutogliptin with or without metformin. The GMR (dutogliptin + metformin/metformin) of AUC(0-12h) at steady state was 0.99 (90% CI: 0.84-1.17; p = 0.93); the GMR of C(max) was 0.91 (90% CI: 0.79-1.04; p = 0.18); T(max) was comparable for metformin with or without dutogliptin. Metformin added to dutogliptin had no effect on plasma DPP4 inhibition. All three treatment regimens were well tolerated.


CONCLUSIONS
In this small, multiple dose study, the steady state pharmacokinetics of either dutogliptin or metformin were not altered by co-administration of the two agents. Dutogliptin and metformin were well tolerated either alone or in combination and co-administered metformin did not alter the ex vivo DPP4 inhibition by dutogliptin. There is no need to consider pharmacokinetic and pharmacodynamic interactions when determining the dosage of either agent for co-administration. A phase 3 clinical trial is underway to provide more definitive data on the safety and efficacy of dutogliptin administered on a background of metformin treatment.
Li
Jianke
J
Pharmacokinetics, Dynamics & Metabolism, Phenomix Corporation, San Diego, CA 92121, USA. Jack.Li@phenomixcorp.com
Klemm
Kirsti
K
O'Farrell
A Marie
AM
Guler
Hans-Peter
HP
Cherrington
Julie M
JM
Schwartz
Sherwyn
S
Boyea
Teresa
T
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008875:Middle Aged
D001897:Boronic Acids; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C552164:dutogliptin; D008687:Metformin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4