Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans
Min-Soo Kim,
Yoo-Kyung Song,
Ji-Soo Choi,
Hye Young Ji,
Eunsuk Yang,
Joon Seok Park,
Hyung Sik Kim,
Min-Joo Kim,
In-Kyung Cho,
Suk-Jae Chung,
Yoon-Jee Chae,
Kyeong-Ryoon Lee
Affiliations
Min-Soo Kim
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Yoo-Kyung Song
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
Ji-Soo Choi
Life Science Institute, Daewoong Pharmaceutical, Yongin 17028, Republic of Korea
Hye Young Ji
Life Science Institute, Daewoong Pharmaceutical, Yongin 17028, Republic of Korea
Eunsuk Yang
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Joon Seok Park
Life Science Institute, Daewoong Pharmaceutical, Yongin 17028, Republic of Korea
Hyung Sik Kim
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Min-Joo Kim
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
In-Kyung Cho
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
Suk-Jae Chung
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Yoon-Jee Chae
College of Pharmacy, Woosuk University, Wanju-gun 55338, Republic of Korea
Kyeong-Ryoon Lee
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration–time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction.
