Koichi Hirao1, Hajime Maeda1, Shinichi Urata1, Yukiko Takisawa1, Setsuko Hirao1, Tatsuya Sasako2, Tomio Sasaki3. 1. Department of Internal Medicine, H. E C. Science Clinic, Yokohama, Japan. 2. Development Division, Department of Diabetes Clinical Development, Novo Nordisk Pharma Ltd., Tokyo, Japan. 3. Development Division, Department of Diabetes Clinical Development, Novo Nordisk Pharma Ltd., Tokyo, Japan. Electronic address: tosa@novonordisk.com.
Abstract
BACKGROUND: To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid-acting component soluble IAsp) and intermediate-acting component (protamine-crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. METHODS: This single-center, randomized, doubleblind, 2-period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged > or = 20 years with a > or = 1 year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [C(max,IAsp); primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC(0-120 min,IAspl), AUC(0-240 min,IAsp), and AUC(0-480 min,IAsp5) respectively], and time to (Cmax,IAsp) [T(max,IAsp)] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC(0-120 min,GIR)), maximum GIR (GIR(max)), and time to GIRmax (T(max,GIR)). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). RESULTS:Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m(2); mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). Mean(Cmax,IAsp) with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC(0-120 min,IAsp) was 1.68 (95% CI, 1.31-2.14). The BIAsp50/BIAsp30 ratiofor AUC(0-120 min,GIR) was 1.31 (95% CI, 1.02-1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. CONCLUSION: In this small PK/PD study in adults with type 2 diabetes in Japan, mean C(max,IAsp) was significantly higher with BIAsp50 than with BIAsp30, and AUC(0-120 min,IAsp) and AUC(0-120 min,GIR) were higher with BIAsp50 than with BIAsp30.
RCT Entities:
BACKGROUND: To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid-acting component soluble IAsp) and intermediate-acting component (protamine-crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. METHODS: This single-center, randomized, doubleblind, 2-period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged > or = 20 years with a > or = 1 year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [C(max,IAsp); primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC(0-120 min,IAspl), AUC(0-240 min,IAsp), and AUC(0-480 min,IAsp5) respectively], and time to (Cmax,IAsp) [T(max,IAsp)] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC(0-120 min,GIR)), maximum GIR (GIR(max)), and time to GIRmax (T(max,GIR)). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). RESULTS: Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m(2); mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). Mean(Cmax,IAsp) with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC(0-120 min,IAsp) was 1.68 (95% CI, 1.31-2.14). The BIAsp50/BIAsp30 ratiofor AUC(0-120 min,GIR) was 1.31 (95% CI, 1.02-1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. CONCLUSION: In this small PK/PD study in adults with type 2 diabetes in Japan, mean C(max,IAsp) was significantly higher with BIAsp50 than with BIAsp30, and AUC(0-120 min,IAsp) and AUC(0-120 min,GIR) were higher with BIAsp50 than with BIAsp30.