PMID- 31026084
OWN - NLM
STAT- MEDLINE
DCOM- 20200824
LR  - 20210109
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 85
IP  - 8
DP  - 2019 Aug
TI  - Pharmacokinetic and pharmacodynamic modelling for renal function dependent 
      urinary glucose excretion effect of ipragliflozin, a selective sodium-glucose 
      cotransporter 2 inhibitor, both in healthy subjects and patients with type 2 
      diabetes mellitus.
PG  - 1808-1819
LID - 10.1111/bcp.13972 [doi]
AB  - AIMS: To provide a model-based prediction of individual urinary glucose excretion 
      (UGE) effect of ipragliflozin, we constructed a pharmacokinetic/pharmacodynamic 
      (PK/PD) model and a population PK model using pooled data of clinical studies. 
      METHODS: A PK/PD model for the change from baseline in UGE for 24 hours 
      (DeltaUGE(24h) ) with area under the concentration-time curve from time of dosing to 
      24 h after administration (AUC(24h) ) of ipragliflozin was described by a maximum 
      effect model. A population PK model was also constructed using rich PK sampling 
      data obtained from 2 clinical pharmacology studies and sparse data from 4 
      late-phase studies by the NONMEM $PRIOR subroutine. Finally, we simulated how the 
      PK/PD of ipragliflozin changes in response to dose regime as well as patients' 
      renal function using the developed model. RESULTS: The estimated individual 
      maximum effect were dependent on fasting plasma glucose and renal function, 
      except in patients who had significant UGE before treatment. The PK of 
      ipragliflozin in type 2 diabetes mellitus (T2DM) patients was accurately 
      described by a 2-compartment model with first order absorption. The population 
      mean oral clearance was 9.47 L/h and was increased in patients with higher 
      glomerular filtration rates and body surface area. Simulation suggested that 
      medians (95% prediction intervals) of AUC(24h) and DeltaUGE(24h) were 5417 
      (3229-8775) ng.h/mL and 85 (51-145) g, respectively. The simulation also 
      suggested a 1.17-fold increase in AUC(24h) of ipragliflozin and a 0.76-fold in 
      DeltaUGE(24h) in T2DM patients with moderate renal impairment compared to those with 
      normal renal function. CONCLUSIONS: The developed models described the clinical 
      data well, and the simulation suggested mechanism-based weaker antidiabetic 
      effect in T2DM patients with renal impairment.
CI  - (c) 2019 Astellas Pharma Inc. British Journal of Clinical Pharmacology published by 
      John Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Saito, Masako
AU  - Saito M
AUID- ORCID: 0000-0001-5062-9905
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Kaibara, Atsunori
AU  - Kaibara A
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Kadokura, Takeshi
AU  - Kadokura T
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Toyoshima, Junko
AU  - Toyoshima J
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Yoshida, Satoshi
AU  - Yoshida S
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Kazuta, Kenichi
AU  - Kazuta K
AD  - Astellas Pharma Inc., Tokyo, Japan.
FAU - Ueyama, Eiji
AU  - Ueyama E
AD  - Astellas Pharma Inc., Tokyo, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190620
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Blood Glucose)
RN  - 0 (Glucosides)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 0 (Thiophenes)
RN  - 3N2N8OOR7X (ipragliflozin)
SB  - IM
MH  - Administration, Oral
MH  - Aged
MH  - Area Under Curve
MH  - Blood Glucose/analysis/*metabolism
MH  - Diabetes Mellitus, Type 2/blood/*drug therapy/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Glomerular Filtration Rate/physiology
MH  - Glucosides/*pharmacology/therapeutic use
MH  - Healthy Volunteers
MH  - Humans
MH  - Kidney/metabolism/physiopathology
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Renal Elimination/*drug effects
MH  - Sodium-Glucose Transporter 2 Inhibitors/*pharmacology/therapeutic use
MH  - Thiophenes/*pharmacology/therapeutic use
PMC - PMC6624389
OTO - NOTNLM
OT  - Suglat
OT  - ipragliflozin
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - sodium-glucose cotransporter 2 inhibitor
OT  - type 2 diabetes mellitus
COIS- All authors are employees of Astellas Pharma Inc., Tokyo, Japan.
EDAT- 2019/04/27 06:00
MHDA- 2020/08/25 06:00
PMCR- 2019/06/20
CRDT- 2019/04/27 06:00
PHST- 2018/11/02 00:00 [received]
PHST- 2019/03/22 00:00 [revised]
PHST- 2019/04/04 00:00 [accepted]
PHST- 2019/04/27 06:00 [pubmed]
PHST- 2020/08/25 06:00 [medline]
PHST- 2019/04/27 06:00 [entrez]
PHST- 2019/06/20 00:00 [pmc-release]
AID - BCP13972 [pii]
AID - 10.1111/bcp.13972 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2019 Aug;85(8):1808-1819. doi: 10.1111/bcp.13972. Epub 2019 
      Jun 20.