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(0-4 hours) of IN insulin was in the range of 10% to 30%, and observed Tmax was in the range of 30 minutes or lower, compared with about 50 minutes for NovoLog. IN insulin achieved a maximum glucose fall faster (*56 minutes) than SC Novolog (*88 minutes) or Exubera (*100 minutes). The bioavailability of various IN insulin formulations dosed in humans was compared with the data generated from rabbit studies (Fig. 2B), and there was a good correlation between the two species.

Recently, we have reported positive phase 2 data for IN insulin (115), comparing the PK and PD effect versus insulin aspart administered by subcutaneous (SC) injection (NovoLog, Novo Nordisk Inc., Princeton, New Jersey, U.S.A.) on postprandial glycemic control and evaluating of the incidence of hypoglyce-mia within four hours post dosing. Each patient ate a standard breakfast and then underwent a series of drug challenges including placebo, and optimized insulin aspart dose and an optimized IN insulin dose. Both IN insulin and insulin aspart provided statistically significant postmeal glucose reduction at 60 and 90 minutes compared with usual oral antidiabetic therapy (Fig. 3). IN insulin was noninferior to insulin aspart for postmeal change from baseline glucose levels at 60 and 90 minutes. The mean change from baseline at the 60-minute time point was 56.9 mg/dL and 62.9 mg/dL for IN insulin and insulin aspart, respectively. The percent CVs (intersubject variability) for PK (blood insulin levels) and PD (postmeal glucose) were similar for IN insulin and insulin aspart.

The Tmax for IN insulin was significantly faster (p < 0.001) than that for insulin aspart, with blood levels for IN insulin seen as fast as five minutes post dose. The median time to peak concentrations for IN insulin was 30 minutes, compared with that of 90 minutes for insulin aspart. IN insulin was well

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FIGURE 3 Insulin pharmacodynamics in humans for IN formulation (black line), insulin aspart (gray line), and usual therapy (dash line). With respect to postmeal glucose at the 60- and 90-minute postmeal time points, the study demonstrated that both insulin aspart and IN insulin were significantly better than placebo at lowering postmeal glucose and that IN insulin was noninferior to insulin aspart. IN insulin results in statistically significant postmeal glucose reduction compared with usual therapy at 60 and 90 minutes. The glucose reduction following IN insulin is noninferior to that following insulin aspart at 60 minutes and 90 minutes. Abbreviation: IN, intranasal. Source: From Ref. 115.

tolerated with only one adverse event reported (one patient sneezed 19 minutes after dosing) out of 146 nasal administrations.

There was a statistically significant decrease in the incidence of patients experiencing hypoglycemia (blood glucose <70 mg/dL) for IN insulin (1 of 29) compared with that for insulin aspart (6 of 29) (p < 0.05). These data indicate that, when compared with insulin aspart, IN insulin provides equivalent gly-cemic control with lower risk of hypoglycemia.

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