Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules.
Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%-60% after the oral administration of clinical doses (100-300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%-0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin-treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd.
Showa Pharmaceutical University, Machida, Tokyo, Japan. mori.kazumi@ma.mt-pharma.co.jp.|Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan. mori.kazumi@ma.mt-pharma.co.jp.
Kazumi
K
Mori
Showa Pharmaceutical University, Machida, Tokyo, Japan.|Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan.
Ryuta
R
Saito
Showa Pharmaceutical University, Machida, Tokyo, Japan.|Mitsubishi Tanabe Pharma Corporation, Chuo-ku, Tokyo, Japan.
Yoshinobu
Y
Nakamaru
Showa Pharmaceutical University, Machida, Tokyo, Japan.
Makiko
M
Shimizu
Showa Pharmaceutical University, Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp.
Hiroshi
H
Yamazaki
D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000068896:Canagliflozin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005544:Forecasting; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D055815:Young Adult
D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin
PBPK/PD modeling; SGLT1; SGLT2; proximal tubule; small intestine