Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

Abstract

Chiglitazar (CHI) is a potent and selective peroxisome proliferator‐activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open‐label, randomized, 3‐period crossover and self‐controlled study was conducted to investigate drug‐drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial. The area under the plasma concentration‐time curves from time 0 to 48 hours (AUC0‐48 h) of CHI was similar following administration alone or with MET (AUC0‐48h, 12 540 ng·h/mL [9811‐15 269 ng·h/mL] vs 12 130 ng·h/mL [9304‐14 956 ng·h/mL]; 90% confidence interval [CI] of its geometric mean ratio [GMR], 89.7%–103.8%), whereas the maximum concentration (Cmax) of CHI was reduced during coadministration, as its 90%CI of the GMR was slightly outside the acceptance range for bioequivalence (Cmax, 1620 ng/mL [1418‐1822 ng/mL] vs 1420 ng/mL [1049‐1791 ng/mL], 90%CI GMR, 77.%‐94.1%). However, it was not considered clinically meaningful. The MET exposures remained consistent in the absence or presence of CHI (AUC0‐48 h, 12 570 ng·h/mL [10681‐14 459 ng·h/mL] vs 13 190 [10973‐15 407 ng·h/mL); 90%CI of GMR: 99.1%‐110.5%; Cmax, 1790 ng/mL [1448–2132 ng/mL] vs 1820 ng/mL [1510‐2130 ng/mL]; 90%CI of GMR, 94.2%–110.9%). No moderate to severe adverse events were reported. Our study indicated no clinically significant pharmacokinetic drug‐drug interaction between CHI and MET and demonstrated good tolerance in subjects. These results support future application of CHI in combination with MET for treatment of T2DM.

Pharmacokinetics and Safety of Chiglitazar, a Peroxisome Proliferator‐Activated Receptor Pan‐Agonist, in Patients < 65 and ≥ 65 Years With Type 2 Diabetes

“…The plasma concentration of chiglitazar was determined by a validated high‐performance liquid chromatography coupled with tandem mass spectrometry method. Chiglitazar and the internal standard (the internal standard was the same as in the previous study 18 ) were extracted from plasma by protein precipitation. The analytes were eluted via a Luna C8 column (50 × 20 mm, 5 μm) with a varying gradient mobile phase of acetonitrile and 0.4% formic acid (pH 3.2).…”

“…Within 96 hours after oral administration of 3 H‐chiglitazar, the radioactivity excreted in urine and feces in rats was 25% and 66% of the dose, respectively. No significant inhibition and induction effect on drug‐metabolizing enzymes was found 18,21 . Previous clinical studies have shown that chiglitazar has favorable linear pharmacokinetic properties in healthy subjects following ascending single dosing of 8‐72 mg 21 and no significant pharmacokinetic drug‐drug interaction between chiglitazar and metformin 18 .…”

“…No significant inhibition and induction effect on drug‐metabolizing enzymes was found 18,21 . Previous clinical studies have shown that chiglitazar has favorable linear pharmacokinetic properties in healthy subjects following ascending single dosing of 8‐72 mg 21 and no significant pharmacokinetic drug‐drug interaction between chiglitazar and metformin 18 . However, the understanding of chiglitazar pharmacokinetics in elderly T2DM patients is still inadequate.…”

“…Chiglitazar, a configuration‐restricted nonthiazolidinedione peroxisome proliferator‐activated receptor (PPAR) pan‐agonist (the structure was shown in a previous study 18 ) is designed for the treatment of T2DM. Currently, chiglitazar has completed the phase 3 clinical development in China (ClinicalTrials.gov identifier: NCT02121717 and NCT02173457).…”

A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators

“… ( a ) Predicted plasma concentrations of metformin following different dosage of human. ( b ) Predicted (line) and observed (point) relationship between metformin dose and dose/AUC for different dose; shaded area, 0.5–2.0 folds of prediction; observations were cited from [ 13 , 15 , 16 , 19 , 20 , 27 , 68 , 69 , 84 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 ]. ( c ) Visual predictive checks (VPCs) of metformin plasma concentrations to time in 500 mg oral administration for human; solid line, the 50th percentiles; dashed lines, the 5 and 95th percentiles of the simulated populations; the shaded area, 90% confidence intervals of the simulated concentrations of the 5, 50 and 95th percentiles; and the point, observations, which were cited from [ 27 , 69 , 91 , 93 , 97 , 114 ].…”