PMID- 18405788 OWN - NLM STAT- MEDLINE DCOM- 20081001 LR - 20221207 IS - 0149-2918 (Print) IS - 0149-2918 (Linking) VI - 30 IP - 3 DP - 2008 Mar TI - Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. PG - 499-512 LID - 10.1016/j.clinthera.2008.03.004 [doi] AB - BACKGROUND: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). OBJECTIVES: This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values. RESULTS: Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. CONCLUSIONS: In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity. FAU - Covington, Paul AU - Covington P AD - Pharmaceutical Product Development, Inc., Wilmington, North Carolina, USA. FAU - Christopher, Ronald AU - Christopher R FAU - Davenport, Michael AU - Davenport M FAU - Fleck, Penny AU - Fleck P FAU - Mekki, Qais A AU - Mekki QA FAU - Wann, Elisabeth R AU - Wann ER FAU - Karim, Aziz AU - Karim A LA - eng PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Blood Glucose) RN - 0 (C-Peptide) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glycated Hemoglobin A) RN - 0 (Insulin) RN - 0 (Piperidines) RN - 0 (Placebos) RN - 4429-04-3 (Fructosamine) RN - 56HH86ZVCT (Uracil) RN - JHC049LO86 (alogliptin) SB - IM MH - Adult MH - Aged MH - Blood Glucose/drug effects MH - C-Peptide/blood/drug effects MH - Diabetes Mellitus, Type 2/blood/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/adverse effects/pharmacokinetics/*pharmacology MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Fructosamine/blood MH - Glycated Hemoglobin/drug effects MH - Humans MH - Insulin/blood MH - Male MH - Middle Aged MH - Piperidines/adverse effects/pharmacokinetics/*pharmacology MH - Placebos/administration & dosage MH - Time Factors MH - Treatment Outcome MH - Uracil/adverse effects/*analogs & derivatives/pharmacokinetics/pharmacology EDAT- 2008/04/15 09:00 MHDA- 2008/10/02 09:00 CRDT- 2008/04/15 09:00 PHST- 2008/01/15 00:00 [accepted] PHST- 2008/04/15 09:00 [pubmed] PHST- 2008/10/02 09:00 [medline] PHST- 2008/04/15 09:00 [entrez] AID - S0149-2918(08)00117-3 [pii] AID - 10.1016/j.clinthera.2008.03.004 [doi] PST - ppublish SO - Clin Ther. 2008 Mar;30(3):499-512. doi: 10.1016/j.clinthera.2008.03.004.