title: Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin.
abstract: OBJECTIVE
  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.
authors.affiliation: Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Naik
authors.affiliation: Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Czerniak
authors.affiliation: Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA.
authors.forename: Majid
authors.initials: M
authors.lastname: Vakilynejad
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D001835:Body Weight; D017321:Clinical Trials, Phase I as Topic; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D010880:Piperidines; D014498:Uracil; C520853:alogliptin
keywords: DPP-4 inhibitor; alogliptin; renal function; type 2 diabetes mellitus