Abstract
Objective
The aim of this study was to examine the effect of ketoconazole, a potent cytochrome
P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics
and to evaluate the safety of combined administration of teneligliptin with ketoconazole.
Methods
This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers
in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered
to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8–10), 400
mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and
ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13),
ketoconazole was administered once daily. The pharmacokinetic parameters (Cmax, Tmax, AUC, terminal t½, apparent total plasma clearance, and Vd during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The
safety profile was evaluated based on adverse events and clinical findings. To investigate
the role of human P-gp in membrane permeation of teneligliptin, an in vitro study
was performed to measure the transcellular transport of teneligliptin across monolayers
of human P-gp-expressing cells and control cells.
Results
For Cmax and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with
ketoconazole to teneligliptin alone were 1.37 (1.25–1.50) and 1.49 (1.39–1.60), respectively.
There was no change in t½ of the terminal elimination phase. In addition, the tolerability of teneligliptin
coadministered with ketoconazole was acceptable. The in vitro study revealed corrected
efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of
1 and 10 μM, respectively.
Conclusions
Because the exposure to teneligliptin in combined administration with ketoconazole,
a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of
teneligliptin alone, it is suggested that combined administration of teneligliptin
with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure.
The results of our in vitro study suggest that teneligliptin is a substrate of P-gp.
Clinical Trial Registration: EudraCT No. 2009-016652-51.
Key words
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Article info
Publication history
Published online: April 09, 2014
Accepted:
March 7,
2014
Identification
Copyright
© 2014 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
