title: Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats.
abstract: Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. The importance of the PK profile of PPARγ agonist was evaluated for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (q.d.) or once every other day (q.2d.) as double the amount for the q.d.
  
  
  METHODS
  The plasma glucose lowering effect was selected as a surrogate PD effect for an anti-diabetic effect. The model fitting was conducted using the non-linear mixed effect modeling (NONMEM) method. The indirect response model described well the plasma glucose concentration-time profile. The q.d. treatment showed a stronger impact on the plasma glucose lowering effect than did the q.2d.
  
  
  METHODS
  The results of PK/PD modeling suggested that the sensitivity (i.e. EC50) between each group was comparable. On the other hand, the time above the effective concentration in the q.d. treatment group was longer than that in the q.2d. treatment group. The simulation of various dose regimens suggested that the much longer exposure duration within the effective level showed a stronger plasma glucose lowering effect, even with identical exposure to pioglitazone in the plasma. The PK/PD analysis clarified that the PK profile affected the pharmacological response and that continuous exposure at an appropriate effective level would be efficient for the anti-diabetic effect of the PPARγ agonist.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Akihiko
authors.identifier: http://orcid.org/0000-0001-6294-4961
authors.initials: A
authors.lastname: Goto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kogame
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: PK profile; PK/PD; PPAR; diabetes; modeling and simulation