PMID- 26617339
OWN - NLM
STAT- MEDLINE
DCOM- 20161215
LR  - 20210109
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 81
IP  - 4
DP  - 2016 Apr
TI  - Application of pharmacometric approaches to evaluate effect of weight and renal 
      function on pharmacokinetics of alogliptin.
PG  - 700-12
LID - 10.1111/bcp.12853 [doi]
AB  - AIMS: The aims of the study were to characterize the pharmacokinetics (PK) of 
      alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a 
      population PK approach and to assess the influence of various covariates on 
      alogliptin exposure. METHODS: Plasma concentration data collected from two phase 
      1 studies and one phase 3 study following administration of alogliptin 
      (12.5-400 mg) were used for the PK model development. One- and two-compartment 
      models were evaluated as base structural PK models. The impact of selected 
      covariates was assessed using stepwise forward selection and backward elimination 
      procedures. The predictability and robustness of the final model was evaluated 
      using visual predictive check and bootstrap analyses. The final model was used to 
      perform simulations and guide appropriate dose adjustments. RESULTS: A 
      two-compartment model with first-order absorption and elimination best described 
      the alogliptin concentration vs. time profiles. Creatinine clearance and weight 
      had a statistically significant effect on the oral clearance (CL/F) of 
      alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher 
      systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe 
      renal impairment, respectively, compared with healthy subjects. Effect of weight 
      on CL/F was not considered clinically relevant. Simulations at different doses of 
      alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with 
      moderate and severe renal impairment, respectively. CONCLUSIONS: The PK of 
      alogliptin was well characterized by the model. The analysis suggested an 
      alogliptin dose adjustment for subjects with moderate-to-severe renal impairment 
      and no dose adjustments based on weight.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Naik, Himanshu
AU  - Naik H
AD  - Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, 
      IL, 60015, USA.
FAU - Czerniak, Richard
AU  - Czerniak R
AD  - Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, 
      IL, 60015, USA.
FAU - Vakilynejad, Majid
AU  - Vakilynejad M
AD  - Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, 
      IL, 60015, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160222
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Piperidines)
RN  - 56HH86ZVCT (Uracil)
RN  - JHC049LO86 (alogliptin)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Biological Availability
MH  - *Body Weight
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Diabetes Mellitus, Type 2/blood/drug therapy
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Hypoglycemic Agents/administration & dosage/blood/*pharmacokinetics/therapeutic 
      use
MH  - Kidney/*metabolism
MH  - Kidney Function Tests
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Piperidines/administration & dosage/blood/*pharmacokinetics/therapeutic use
MH  - Tissue Distribution
MH  - Uracil/administration & dosage/*analogs & 
      derivatives/blood/pharmacokinetics/therapeutic use
MH  - Young Adult
PMC - PMC4799927
OTO - NOTNLM
OT  - DPP-4 inhibitor
OT  - alogliptin
OT  - renal function
OT  - type 2 diabetes mellitus
EDAT- 2015/12/01 06:00
MHDA- 2016/12/16 06:00
PMCR- 2017/04/01
CRDT- 2015/12/01 06:00
PHST- 2015/08/21 00:00 [received]
PHST- 2015/11/13 00:00 [revised]
PHST- 2015/11/26 00:00 [accepted]
PHST- 2015/12/01 06:00 [entrez]
PHST- 2015/12/01 06:00 [pubmed]
PHST- 2016/12/16 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - BCP12853 [pii]
AID - 10.1111/bcp.12853 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2016 Apr;81(4):700-12. doi: 10.1111/bcp.12853. Epub 2016 Feb 
      22.