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Afrezza

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Afrezza

CLINICAL PHARMACOLOGY

Mechanism Of Action

Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

Pharmacodynamics

The pharmacodynamic profile for orally inhaled AFREZZA 8 units relative to subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1 diabetes is shown in Figure 3(A). The median time to maximum effect of AFREZZA (measured by the peak rate of glucose infusion) was approximately 53 minutes (standard deviation of 74 minutes) and the effect then declined to near baseline levels by about 160 minutes.

Figure 3: Baseline-Corrected Glucose Infusion Rate (A) and Baseline-Corrected Serum Insulin Concentrations (B) after Administration of AFREZZA or Subcutaneous Insulin Lispro in Type 1 Diabetes Patients*

Baseline-Corrected Glucose Infusion Rate (A) and Baseline-Corrected Serum Insulin Concentrations (B) - Illustration

* Despite the faster absorption of insulin (PK) from Afrezza, the onset of activity (PD) was comparable to insulin lispro.

In a study of 32 healthy subjects, the pharmacodynamic effect of AFREZZA, measured as area under the glucose infusion rate - time curve (AUC-GIR) from an euglycemic clamp, increased in a less than dose-proportional manner. This effect has been observed for subcutaneously administered insulins, but it is unknown if the diminishing pharmacodynamic benefit at higher dosage of AFREZZA parallels that which is seen with subcutaneously administered insulin.

Pharmacokinetics

The insulin contained in AFREZZA is regular human insulin. Following pulmonary absorption into systemic circulation, the metabolism and elimination are comparable to regular human insulin.

Absorption

The pharmacokinetic profiles for orally inhaled AFREZZA 8 units relative to subcutaneously administered insulin lispro 8 units from a study in 12 patients with type 1 diabetes are shown in Figure 3(B). The maximum serum insulin concentration was reached by 12-15 minutes after inhalation of AFREZZA 8 units and serum insulin concentrations declined to baseline by approximately 180 minutes. However, the faster absorption of insulin from Afrezza [see Figure 3(B)] did not result in a faster onset of activity compared to insulin lispro [see Figure 3(A)].

Disposition

Systemic insulin disposition (median terminal half-life) following oral inhalation of AFREZZA 4 and 32 units was 28-39 minutes, and 145 minutes for subcutaneous regular human insulin 15 units.

Carrier Particles

Clinical pharmacology studies showed that carrier particles [see DESCRIPTION] are not metabolized and are eliminated unchanged in the urine following the lung absorption. Following oral inhalation of AFREZZA, a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces.

Drug Interaction

Bronchodilators and Inhaled Steroids

Albuterol increased the AUC insulin administered by AFREZZA by 25% in patients with asthma. Effect of fluticasone on insulin exposures following AFREZZA administration has not been evaluated in patients with asthma; however, no significant change in insulin exposure was observed in a study in healthy volunteers. Frequent glucose monitoring and dose reduction may be necessary for AFREZZA if it is co-administered with albuterol.

Clinical Studies

Overview Of Clinical Studies Of AFREZZA For Diabetes Mellitus

AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin. The efficacy of AFREZZA in type 1 diabetes patients was compared to insulin aspart in combination with basal insulin. AFREZZA has been studied in adults with type 2 diabetes in combination with oral antidiabetic drugs. The efficacy of AFREZZA in type 2 diabetes patients was compared to placebo inhalation.

Type 1 Diabetes

Patients with inadequately controlled type 1 diabetes participated in a 24-week, open-label, active-controlled study to evaluate the glucose lowering effect of mealtime AFREZZA used in combination with a basal insulin. Following a 4-week basal insulin optimization period, 344 patients were randomized to AFREZZA (n=174) or insulin aspart (n=170)administered at each meal of the day. Mealtime insulin doses were titrated to glycemic goals for the first 12 weeks and kept stable for the last 12 weeks of the study. At Week 24, treatment with basal insulin and mealtime AFREZZA provided a mean reduction in HbA1c that met the prespecified non-inferiority margin of 0.4%. AFREZZA provided less HbA1c reduction than insulin aspart, and the difference was statistically significant. More subjects in the insulin aspart group achieved the HbA1c target of ≤ 7% (Table 4).

Table 4: Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA plus Basal Insulin in Adults with Type 1 Diabetes

Efficacy Parameter AFREZZA + Basal Insulin
(N=174)
Insulin Aspart + Basal Insulin
(N=170)
HbA1c (%)
  Baseline (adjusted meana) 7.94 7.92
  Change from baseline (adjusted meana,b) -0.21 -0.40
  Difference from insulin aspart (adjusted meana,b) (95% CI) 0.19 (0.02, 0.36)
  Percentage of patients achieving HbA1c ≤ 7%c 13.8 27.1
Fasting Plasma Glucose (mg/dL)
  Baseline (adjusted meana) 153.9 151.6
  Change from baseline at (adjusted meana, b) -25.3 10.2
  Difference from insulin aspart (adjusted meana, b) (95% CI) -35.4 (-56.3, -14.6)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks were available from 131 (75 %) and 150 (88% ) subjects randomized to the AFREZZA and insulin aspart groups, respectively.
c The percentage was calculated based on the number of patients randomized to the trial.

Type 2 Diabetes

A total of 479 adult patients with type 2 diabetes inadequately controlled on optimal/maximally tolerated doses of metformin only, or 2 or more oral antidiabetic (OAD) agents participated in a 24-week, double-blind, placebo-controlled study. Following a 6-week run-in period, 353 patients were randomized to AFREZZA (n=177) or an inhaled placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. OADs doses were kept stable. At Week 24, treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was statistically significantly greater compared to the HbA1c reduction observed in the placebo group (Table 5).

Table 5: Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents

Efficacy Parameter AFREZZA + Oral Anti-Diabetic Agents
(N=177)
Placebo + Oral Anti-Diabetic Agents
(N=176)
HbA1c (%)
  Baseline (adjusted meana) 8.25 8.27
  Change from baseline (adjusted meana,b) -0.82 -0.42
  Difference from placebo (adjusted meana,b) (95% CI) -0.40 (-0.57, -0.23)
  Percentage (%) of patients achieving HbA1C ≤ 7%c 32.2 15.3
Fasting Plasma Glucose (mg/dL)
  Baseline (adjusted meana) 175.9 175.2
  Change from baseline (adjusted meana,b) -11.2 -3.8
  Difference from placebo (adjusted meana,b) (95% CI) -7.4 (-18.0, 3.2)
a Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used.
b Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) subjects randomized to the AFREZZA and placebo groups, respectively.
c The percentage was calculated based on the number of patients randomized to the trial.

Last reviewed on RxList: 7/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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