NovoLog (Page 4 of 8)

12.3 Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in NovoLog reduces the molecule’s tendency to form hexamers as observed with regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to regular human insulin.

In a randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the regular human insulin group.

Bioavailability and Absorption — NovoLog has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection (see Figure 2 and Figure 4). The relative bioavailability of NovoLog compared to regular human insulin indicates that the two insulins are absorbed to a similar extent.

Fig. 4 -- Pharmacokinetics Graph showing Bioavailability and Absorption of NovoLog
(click image for full-size original)

Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.

In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as regular human insulin. The median time to maximum concentration in these trials was 40 to 50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In a clinical trial in patients with type 1 diabetes, NovoLog and regular human insulin, both administered subcutaneously at a dose of 0.15 U/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin aspart have not been established in patients with type 2 diabetes.

The intra-individual variability in time to maximum serum insulin concentration for healthy male volunteers was significantly less for NovoLog than for regular human insulin. The clinical significance of this observation has not been established.

In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between NovoLog and regular human insulin described above, were observed independent of the site of injection (abdomen, thigh, or upper arm).

Distribution and Elimination — NovoLog has low binding to plasma proteins (<10%), similar to that seen with regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.

Specific Populations

Children and Adolescents — The pharmacokinetic and pharmacodynamic properties of NovoLog and regular human insulin were evaluated in a single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years [Tanner grade > 2], n=9) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes between NovoLog and regular human insulin were similar to those in healthy adult subjects and adults with type 1 diabetes.

Gender — In healthy volunteers, no difference in insulin aspart levels was seen between men and women when body weight differences were taken into account. There was no significant difference in efficacy noted (as assessed by HbAlc ) between genders in a trial in patients with type 1 diabetes.

Obesity — A single subcutaneous dose of 0.1 U/kg NovoLog was administered in a study of 23 patients with type 1 diabetes and a wide range of body mass index (BMI, 22-39 kg/m2). The pharmacokinetic parameters, AUC and Cmax , of NovoLog were generally unaffected by BMI in the different groups – BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2 (N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.

Renal Impairment — Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. A single subcutaneous dose of 0.08 U/kg NovoLog was administered in a study to subjects with either normal (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr = 50-80 ml/min), moderate (N=3; CLcr = 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment. In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4) ].

Hepatic Impairment — Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. A single subcutaneous dose of 0.06 U/kg NovoLog was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5) ].

The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and pharmacodynamics of NovoLog has not been studied.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for NovoLog was not significantly different than for regular human insulin. The relevance of these findings to humans is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and female rats, at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

13.2 Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is more rapid in onset and of shorter duration, compared to regular human insulin, due to its faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY Figure 2 and Figure 4).

14 CLINICAL STUDIES

14.1 Subcutaneous Daily Injections

Two six-month, open-label, active-controlled studies were conducted to compare the safety and efficacy of NovoLog to Novolin R in adult patients with type 1 diabetes. Because the two study designs and results were similar, data are shown for only one study (see Table 3). NovoLog was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events requiring intervention from a third party) were comparable for the two treatment regimens in this study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic ketoacidosis was not reported in any of the adult studies in either treatment group.

Table 3. Subcutaneous NovoLog Administration in Type 1 Diabetes (24 weeks; n=882)
*
Values are Mean ± SD
Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

NovoLog + NPH

Novolin R + NPH

N

596

286

Baseline HbA1c (%)*

7.9 ±1.1

8.0 ± 1.2

Change from Baseline HbA1c (%)

-0.1 ± 0.8

0.0 ± 0.8

Treatment Difference in HbA1c , Mean (95% confidence interval)

-0.2 (-0.3, -0.1)

Baseline insulin dose (IU/kg/24 hours)*

0.7 ± 0.2

0.7 ± 0.2

End-of-Study insulin dose (IU/kg/24 hours)*

0.7 ± 0.2

0.7 ± 0.2

Patients with severe hypoglycemia (n, %)

104 (17%)

54 (19%)

Baseline body weight (kg)*

Weight Change from baseline (kg)*

75.3 ± 14.5

0.5 ± 3.3

75.9 ± 13.1

0.9 ± 2.9

A 24-week, parallel-group study of children and adolescents with type 1 diabetes (n = 283) aged 6 to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog (n = 187) or Novolin R (n = 96). NPH insulin was administered as the basal insulin. NovoLog achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4) and both treatment groups had a comparable incidence of hypoglycemia. Subcutaneous administration of NovoLog and regular human insulin have also been compared in children with type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c and hypoglycemia.

Table 4. Pediatric Subcutaneous Administration of NovoLog in Type 1 Diabetes (24 weeks; n=283)
*
Values are Mean ± SD
Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

NovoLog + NPH

Novolin R + NPH

N

187

96

Baseline HbA1c (%)*

8.3 ± 1.2

8.3 ± 1.3

Change from Baseline HbA1c (%)

0.1± 1.0

0.1± 1.1

Treatment Difference in HbA1c, Mean (95% confidence interval)

0.1 (-0.5, 0.1)

Baseline insulin dose (IU/kg/24 hours)*

0.4 ± 0.2

0.6 ± 0.2

End-of-Study insulin dose (IU/kg/24 hours)*

0.4 ± 0.2

0.7 ± 0.2

Patients with severe hypoglycemia (n, %)

11 (6%)

9 (9%)

Diabetic ketoacidosis (n, %)

10 (5%)

2 (2%)

Baseline body weight (kg)*

Weight Change from baseline (kg)*

50.6 ± 19.6

2.7 ± 3.5

48.7 ± 15.8

2.4 ± 2.6

One six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of NovoLog to Novolin R in patients with type 2 diabetes (Table 5). NovoLog was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and the rates of severe hypoglycemia (as determined from the number of events requiring intervention from a third party) were comparable for the two treatment regimens.

Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6 months; n=176)
*
Values are Mean ± SD
Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

NovoLog + NPH

Novolin R + NPH

N

90

86

Baseline HbA1c (%)*

8.1 ± 1.2

7.8 ± 1.1

Change from Baseline HbA1c (%)

-0.3 ± 1.0

-0.1 ± 0.8

Treatment Difference in HbA1c, Mean (95% confidence interval)

– 0.1 (-0.4, -0.1)

Baseline insulin dose (IU/kg/24 hours)*

0.6 ± 0.3

0.6 ± 0.3

End-of-Study insulin dose (IU/kg/24 hours)*

0.7 ± 0.3

0.7 ± 0.3

Patients with severe hypoglycemia (n, %)

9 (10%)

5 (8%)

Baseline body weight (kg)*

Weight Change from baseline (kg)*

88.4 ± 13.3

1.2 ± 3.0

85.8 ± 14.8

0.4 ± 3.1

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