Systemic Exposure After Treatment With Alogliptin Comparable in Patients With and Without Type 2 Diabetes: Presented at ACCP

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Title: Systemic Exposure After Treatment With Alogliptin Comparable in Patients With and Without Type 2 Diabetes: Presented at ACCP
URL: http://www.pslgroup.com/dg/22CC16.htm
Doctor's Guide
September 18, 2008

By Crina Frincu-Mallos, PhD

PHILADELPHIA -- September 18, 2008 -- The predicted systemic exposure to alogliptin in patients with type 2 diabetes appears to be comparable to that of healthy subjects after the administration of the same dose, according to results of a population pharmacokinetics (PK) model reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting.

Alogliptin, an investigational drug under development for treatment of diabetes, is a potent, bioavailable, highly selective dipeptidyl peptidase-4 inhibitor, according to study presenter Jinshan Shen, PharmD, Takeda Global Research and Development, Inc., Deerfield, Illinois.

Dr. Shen and colleagues sought to evaluate the population PK of alogliptin in patients with type 2 diabetes when used as a combination therapy with metformin. A secondary objective was to assess the influence of patients' demographic factors, disease-related factors, and concurrent medications on PK parameters for alogliptin, Dr. Shen explained in a poster presentation on September 14.

A total of 840 plasma samples were obtained from 398 patients accrued in a randomised, double-blind, placebo-controlled, phase 3 trial. Patients were a median of 56 years old (range, 23-80 years); the mean weight was 88 kg (range, 45.5-141.6 kg).

The trial was designed to assess the efficacy and safety of alogliptin, alone or when added to metformin, another type 2 diabetes medication. Alogliptin was administered orally at 2 doses, 12.5 mg and 25 mg, once daily, said Dr. Shen.

Dr. Shen noted that 52 samples from 23 patients had to be excluded from the analysis, being outliers.

At baseline, more than half of patients had mild renal impairment with a creatinine clearance (CrCL) between 50 and 80 mL/min. Approximately one-third of patients had normal renal function, defined as a level greater than 80 mL/min.

For the population PK analysis, Dr. Shen and collaborators used nonlinear, mixed-effects modelling to develop a structural PK model. The same model was also used to perform covariate analysis for alogliptin, added Dr. Shen.

The concentration-versus-time data were described by a 2-compartment PK model with first-order absorption and first-order elimination, explained Dr. Shen.

For a typical 70-kg patient, the absorption rate constant (Ka) was 2.56 at hour 1, the apparent oral clearance (CL/F) was 17.8 L/hr, the apparent volume of distribution (Vc/F) was 187 L, and the peripheral volume of distribution (Vp) was 191 L.

The interindividual variability (IIV) was 26.81% on Ka, 27.66% on CL/F, and 11.20% on Vc/F, said Dr. Shen.

The researchers included 3 statistically significant covariate effects in the final model. Two covariates were identified as significant on CL/F, CrCL, and body weight, while 1 covariate, body weight, was significant on Vc/F, explained Dr. Shen.

The final population PK model predicted a 15% reduction in alogliptin CL/F for a typical patient with a body weight of 85 kg and mild renal impairment (n = 209); in patients with moderate renal impairment (n = 32), the CL/F reduction was 30% compared with patients with normal renal function.

The model also predicted a 17% CL/F reduction for a patient with a body weight of 50 kg, whereas in a patient with a body weight of 125 kg, there was a CL/F increase of 19%, according to Dr. Shen.

The terminal elimination half-life for diabetic patients on alogliptin was estimated to be 20.9 hours, similar to the value for healthy subjects.(1) Other exposure measurement values were also comparable to those in healthy subjects, such as the maximum plasma concentration (72.01 ng/mL at 12.5 mg and 135.67 ng/mL at 25 mg).(1)

Based on these predictions, the investigators concluded that body-weight changes were not clinically significant and therefore do not require dose adjustments. Also, the predicted systemic exposure to alogliptin in diabetic patients is comparable to the exposure in healthy subjects, they added.

Funding for this study was provided by Takeda Global Research and Development, Inc.

1. Christopher R et al. Clin Ther. 2008;30:513-527.

[Presentation title: Population Pharmacokinetics of Alogliptin in Type 2 Diabetic Patients. Abstract 65]

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