Methods for administering long-lasting hypoglycemic agents

[0094] Example 1

[0095]This is a single-blind, placebo-controlled dose escalation study in which a pharmaceutical composition comprising SEQ ID NO: 1 (0.25 mg-104 mg) is subcutaneously applied to the abdomen of healthy subjects.

[0096] 39 healthy male and female subjects participated in the study. Five groups of healthy subjects received the following two doses of the pharmaceutical composition comprising SEQ ID NO: 1 with increasing doses via abdominal subcutaneous injection: group 1 (0.25 mg + 1 mg); group 2 (3 mg + 6 mg) ); Group 3 (16mg+24mg); Group 4 (48mg+60mg); and Group 5 (80mg+104mg). In groups 1-4, 6 subjects were randomized to receive the active compound, and 2 subjects were randomized to receive a placebo. In Group 5, 5 subjects were randomized to receive the active compound, and 2 subjects were randomized to receive a placebo. Thus, 29 subjects received active treatment and 10 subjects received placebo. The exposure to the pharmaceutical composition comprising SEQ ID NO: 1 increased in a manner greater than proportional to the dose in the dose range tested. For all doses, the half-life of SEQ ID NO: 1 is approximately 7 days, and the Tmax range is 2-4 days.

[0097] The pharmacokinetic parameters in healthy subjects who received the active compound are summarized in Table 1. The pharmacokinetic data of subjects receiving placebo are not summarized. AUC (Wk 1) represents the area under the concentration versus time curve calculated from the moment of the first dose to one week after the first dose. AUC (Wk 2) represents the area under the concentration versus time curve calculated from the time of the second dose to one week after the second dose. Cmax (Wk 1) represents the maximum concentration observed from the time of the first dose to one week after the first dose. Cmax (Wk 2) represents the maximum concentration observed from the time of the second dose to one week after the second dose.

[0098]

[0099] Example 2

[0100] This is a single-blind, placebo-controlled multi-dose study in subjects with T2DM. 54 male and female subjects participated in the study. The subjects either received dietary control or took metformin, sulfonylurea, or a combination of metformin and sulfonylurea. Subjects who took metformin and/or sulfonylurea before the start of the study were eliminated from these treatments 2 weeks before the first dose. The subjects were randomized to receive a placebo or a pharmaceutical composition comprising SEQ ID NO: 1 by subcutaneous injection once a week for two weeks in the abdomen as follows: Group 1 (9 mg + 9 mg; 4 placebos, 14 active agents) ; Group 2 (16mg+16mg; 5 placebos, 12 active agents); Group 3 (32mg+32mg; 5 placebos, 14 active agents). Forty subjects were randomized to receive active agent treatment, and 14 subjects were randomized to receive placebo.

[0101] 53 subjects completed the study. One subject in Group 2 who was randomized to receive active agent treatment withdrew from the study before the second dose (16 mg) was administered. Another subject in group 2 who was randomized to receive the active agent received only the first dose (16 mg). This subject was not included in the pharmacokinetic analysis. Three subjects were wrongly dosed (two placebo subjects and one subject (32 mg) randomized to receive active agent treatment in group 3). Subjects who were wrongly dosed were not included in any pharmacokinetic analysis.

[0102] For all doses, the half-life of SEQ ID NO: 1 is approximately 4-6 days. The range of Tmax is about 1 to about 5 days after taking the drug, and there is no obvious dose dependence. The pharmacokinetic parameters of subjects receiving the active compound are summarized in figure 1 And table 2. Subjects randomized to receive placebo were not included in figure 1 Or in Table 2.

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[0104] Example 3

[0105] This example provides the pharmacodynamic profile of the subject described in Example 2. The subject received a placebo or a subcutaneous injection of the pharmaceutical composition comprising SEQ ID NO: 1, once a week for two weeks as follows: Group 1 (9 mg + 9 mg; 4 placebos, 14 active agents); Group 2 (16mg+16mg; 5 placebo, 12 active agents); Group 3 (32mg+32mg; 5 placebo, 14 active agents). The subjects were dosed on day 1 and day 8. The effect of SEQ ID NO: 1 on glucose and fructosamine in T2DM subjects was evaluated. Subjects with T2DM were either on diet or taking metformin, sulfonylurea, or a combination of metformin and sulfonylurea, and gave up these treatments 2 weeks before the first dose. Fasting and 24-hour glucose profiles were evaluated at baseline and 24 hours after the first and second doses. Fructosamine was evaluated at baseline and on day 3, day 21, and follow-up after the last dosing (day 56 or 63).

[0106] All subjects who received the correct randomized treatment were included in the pharmacodynamic analysis. One subject in group 2 received the correct dosing on day 1, but withdrew before the second dose. This subject was included in the pharmacokinetic analysis of the data collected before day 8, but was excluded from the PD summary after taking the drug on day 8. Two subjects who were randomized to receive a placebo and were incorrectly administered were excluded from all pharmacodynamic analyses. One subject in group 3 who was randomized to receive 32 mg of the active compound was wrongly administered and was excluded from all pharmacodynamic analyses.

[0107] A clinically and statistically significant decrease in the 24-hour weighted average glucose and fasting plasma glucose (FPG) concentration was observed at all dose levels. Glucose data is shown in Table 3.

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[0109]

[0110] A significant reduction in fructosamine was seen at all dose levels on the 13th and 21st days after administration. Due to the estimated half-life of SEQ ID NO: 1, no decrease is expected at the last follow-up (day 56 or 63). The comparison of fructosamine in T2DM subjects receiving the active compound with placebo subjects is summarized in Table 4.

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