Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone, a thiazolidinedione antihyperglycemic agent, in healthy subjects.
OBJECTIVE
Lobeglitazone as a thiazolidinedione antihyperglycemic agent activates peroxisome proliferator-activated receptor (PPAR) γ and may be suitable as monotherapy or in combination with other antihyperglycemic agents. The primary objective of this study was to investigate potential pharmacokinetic interactions between lobeglitazone and metformin in healthy Korean subjects.


METHODS
A randomized, open-label, multiple-dose, three-treatment, three-period, three-sequence, crossover study was conducted in 24 healthy Korean male volunteers. Serial blood samples were collected after lobeglitazone (0.5 mg/day) and metformin (1000 mg/day) were administered alone or concomitantly for 5 days in each period, and drug concentrations were determined by liquid chromatography-tandem mass spectrometry. CLINICAL TRAIL REGISTRATION NUMBER: NCT01005160.


RESULTS
The steady-state maximum plasma concentrations (C(max, ss); mean ± standard deviation) of lobeglitazone and metformin alone were 29.38 ± 5.25 ng/mL and 1661.84 ± 471.88 ng/mL, respectively; the C(max, ss) during co-administration were 27.15 ± 5.75 ng/mL and 1779.92 ± 405.20 ng/mL, respectively. The steady-state areas under the concentration-time curves during the dose interval (AUC(τ, ss); mean ± standard deviation) of sole administration of lobeglitazone and metformin were 277.53 ± 65.25 ng*h/mL and 9650.27 ± 2089.81 ng*h/mL, respectively. When lobeglitazone and metformin were administered concomitantly, the AUC(τ, ss) were 257.29 ± 60.61 ng*h/mL and 10600.58 ± 1960.40 ng*h/mL, respectively. The geometric mean ratios (90% confidence interval) of co-medication to lobeglitazone alone were 0.92 (0.87-0.97; C(max, ss)) and 0.93 (0.87-0.99; AUC(τ, ss)), and those for co-medication to metformin monotherapy were 1.09 (0.99-1.19; C(max, ss)) and 1.11 (1.04-1.19; AUC(τ, ss)). Both monotherapies and combination therapy were well tolerated; 52 self-resolving, non-serious adverse events were reported from 17 subjects.


CONCLUSIONS
Lobeglitazone did not significantly affect the pharmacokinetics of metformin or vice versa when both drugs were co-administered. Lobeglitazone can be co-administered with metformin without dose adjustment for either agent. Therefore further patient studies are needed to corroborate these results.
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Donghoon
D
Shin
Tae-Eun
TE
Kim
Seo Hyun
SH
Yoon
Joo-Youn
JY
Cho
Sang-Goo
SG
Shin
In-Jin
IJ
Jang
Kyung-Sang
KS
Yu
D000328:Adult; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D056910:Republic of Korea; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; D045162:Thiazolidinediones; D008687:Metformin; C546215:lobeglitazone