Tresiba (Page 5 of 9)

12.3 Pharmacokinetics

Absorption

In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 units/kg of TRESIBA, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (t_max ). After the first dose of TRESIBA, median onset of appearance was around one hour.

Total insulin degludec concentration (i.e., exposure) increased in a dose proportional manner after subcutaneous administration of 0.4 units/kg to 0.8 units/kg TRESIBA. Total and maximum insulin degludec exposure at steady state are comparable between TRESIBA U-100 and TRESIBA U-200 when each is administered at the same units/kg dose.

Insulin degludec concentration reached steady state levels after 3-4 days of TRESIBA administration [see Dosage and Administration (2.2)].

Distribution

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein bound drugs.

Elimination

The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at steady state is approximately 25 hours independent of dose. Degradation of TRESIBA is similar to that of insulin human; all metabolites formed are inactive. The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 units/kg.

Specific Populations

Pediatrics-

Population pharmacokinetic analysis was conducted for TRESIBA using data from 199 pediatric subjects (1 to <18 years of age) with type 1 diabetes. Body weight was a significant covariate affecting the clearance of TRESIBA. After adjusting for body weight, the total exposure of TRESIBA at steady state was independent of age.

Geriatrics –

Pharmacokinetic and pharmacodynamic response of TRESIBA was compared in 13 younger adult (18−35 years) and 14 geriatric (≥65 years) subjects with type 1 diabetes following two 6-day periods of once-daily subcutaneous dosing with 0.4 units/kg dose of TRESIBA or insulin glargine. On average, the pharmacokinetic and pharmacodynamic properties of TRESIBA at steady-state were similar in younger adult and geriatric subjects, albeit with greater between subject variability among the geriatric subjects.

Gender —

The effect of gender on the pharmacokinetics of TRESIBA was examined in an across-trial analysis of the pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of TRESIBA. Overall, there were no clinically relevant differences in the pharmacokinetic properties of insulin degludec between female and male subjects.

Obesity-

The effect of BMI on the pharmacokinetics of TRESIBA was explored in a cross-trial analysis of pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of TRESIBA. For subjects with type 1 diabetes, no relationship between exposure of TRESIBA and BMI was observed. For subjects with type 1 and type 2 diabetes a trend for decrease in glucose-lowering effect of TRESIBA with increasing BMI was observed.

Race and Ethnicity –

TRESIBA has been studied in a pharmacokinetic and pharmacodynamic study in Black or African American subjects not of Hispanic or Latino origin (n=18), White subjects of Hispanic or Latino origin (n=22) and White subjects not of Hispanic or Latino origin (n=23) with type 2 diabetes mellitus conducted using unit/kg doses of TRESIBA. There were no statistically significant differences in the pharmacokinetic and pharmacodynamic properties of TRESIBA between the racial and ethnic groups investigated.

Pregnancy-

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of TRESIBA has not been studied [see Use in Specific Populations (8.1)].

Renal Impairment —

TRESIBA pharmacokinetics was studied in 32 subjects (n=4-8/group) with normal or impaired renal function/end-stage renal disease following administration of a single subcutaneous dose (0.4 units/kg) of TRESIBA. Renal function was defined using creatinine clearance (Clcr) as follows: ≥90 mL/min (normal), 60-89 mL/min (mild), 30-59 mL/min (moderate) and <30 mL/min (severe). Subjects requiring dialysis were classified as having end-stage renal disease (ESRD). Total (AUC_{IDeg,0-120h,SD} ) and peak exposure of TRESIBA were on average about 10-25% and 13-27% higher, respectively in subjects with mild to severe renal impairment except subjects with ESRD who showed similar exposure as compared to subjects with normal renal function. No systematic trend was noted for this increase in exposure across different renal impairment subgroups. Hemodialysis did not affect clearance of TRESIBA (CL/F_IDeg,SD ) in subjects with ESRD [see Use in Specific Populations (8.6)].

Hepatic Impairment —

TRESIBA has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with normal or impaired hepatic function (mild, moderate, and severe hepatic impairment) following administration of a single subcutaneous dose (0.4 units/kg) of TRESIBA. Hepatic function was defined using Child-Pugh Scores ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment). No differences in the pharmacokinetics of TRESIBA were identified between healthy subjects and subjects with hepatic impairment [see Use in Specific Populations (8.7)].

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 insulin degludec. In a 52-week study including human insulin (NPH insulin) as comparator (6.7 units/kg/day), Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 units/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 units/kg/day. Human insulin was dosed at 6.7 units/kg/day. No treatment-related increases in incidences of hyperplasia, benign or malignant tumors were recorded in female mammary glands from rats dosed with insulin degludec and no treatment related changes in the female mammary gland cell proliferation were found using BrdU incorporation. Further, no treatment related changes in the occurrence of hyperplastic or neoplastic lesions were seen in other tissues in animals dosed with insulin degludec when compared to vehicle or human insulin.

Genotoxicity testing of insulin degludec was not performed.

In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin degludec up to 21 units/kg/day (approximately 5 times the human subcutaneous dose of 0.75 units/kg/day, based on units/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.

14 CLINICAL STUDIES

The efficacy of TRESIBA administered once-daily either at the same time each day or at any time each day in patients with type 1 diabetes and used in combination with a mealtime insulin was evaluated in three randomized, open-label, treat-to-target, active-controlled trials in adults and one randomized, open-label, treat-to-target, active-controlled trial in pediatric patients 1 year of age and older. The efficacy of TRESIBA administered once-daily either at the same time each day or at any time each day in adult patients with type 2 diabetes and used in combination with a mealtime insulin or in combination with common oral anti-diabetic agents was evaluated in six randomized, open-label, treat-to-target active-controlled trials.

Adult patients treated with TRESIBA achieved levels of glycemic control similar to those achieved with LANTUS (insulin glargine 100 units/mL) and LEVEMIR (insulin detemir) and achieved statistically significant improvements compared to sitagliptin.

14.1 Type 1 Diabetes – Adult

TRESIBA Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients

Study A

The efficacy of TRESIBA was evaluated in a 52-week randomized, open-label, multicenter trial in 629 patients with type 1 diabetes mellitus (Study A). Patients were randomized to TRESIBA once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling. Insulin aspart was administered before each meal in both treatment arms.

The mean age of the trial population was 43 years and mean duration of diabetes was 18.9 years. 58.5% were male. 93% were White, 1.9% Black or African American. 5.1% were Hispanic. 8.6% of patients had eGFR<60 mL/min/1.73m². The mean BMI was approximately 26.3 kg/m².

At week 52, the difference in HbA_1c reduction from baseline between TRESIBA and insulin glargine U-100 was -0.01% with a 95% confidence interval of [-0.14%; 0.11%] and met the pre-specified non-inferiority margin (0.4%). See Table 6, Study A.

Study B

The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 455 patients with type 1 diabetes mellitus (Study B). Patients were randomized to TRESIBA or insulin detemir once-daily in the evening. After 8 weeks, insulin detemir could be dosed twice-daily. 67.1% used insulin detemir once daily at end of trial. 32.9% used insulin detemir twice daily at end of trial. Insulin aspart was administered before each meal in both treatment arms.

The mean age of the trial population was 41.3 years and mean duration of diabetes was 13.9 years. 51.9% were male. 44.6% were White, 0.4% Black or African American. 4.4% were Hispanic. 4.4% of patients had eGFR<60 mL/min/1.73m². The mean BMI was approximately 23.9 kg/m².

At week 26, the difference in HbA_1c reduction from baseline between TRESIBA and insulin detemir was -0.09% with a 95% confidence interval of [-0.23%; 0.05%] and met the pre-specified non-inferiority margin (0.4%). See Table 6, Study B.

Table 6: Results at Week 52 in a Trial Comparing TRESIBA to Insulin Glargine U-100 (Study A) and Week 26 in a Trial Comparing TRESIBA to Insulin Detemir (Study B) in Adult Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes

	Study A		Study B
	TRESIBA + Insulin aspart	Insulin glargine U-100 + Insulin aspart	TRESIBA + Insulin aspart	Insulin detemir + Insulin aspart
N	472	157	302	153
HbA1c (%)
Baseline	7.7	7.7	8.0	8.0
End of trial	7.3	7.3	7.3	7.3
Adjusted mean change from baseline*	-0.36	-0.34	-0.71	-0.61
Estimated treatment difference [95%CI] TRESIBA — basal insulin U-100	-0.01 [-0.14;0.11]		-0.09 [-0.23;0.05]
Proportion Achieving HbA1c < 7% at Trial End	39.8%	42.7%	41.1%	37.3%
FPG (mg/dL)
Baseline	165	174	178	171
End of trial	141	149	131	161
Adjusted mean change from baseline	-27.6	-21.6	-43.3	-13.5
Daily basal insulin dose
Baseline mean	28 U	26 U	22 U	22 U
Mean dose at end of study	29 U1	31 U1	25 U2	29 U2
Daily bolus insulin dose
Baseline mean	29 U	29 U	28 U	31 U
Mean dose at end of study	32 U1	35 U1	36 U2	41 U2

¹ At Week 52

² At Week 26

^* The change from baseline to end of treatment visit in HbA_1c was analyzed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA_1c as covariates.

In Study A, there were 14.8% of subjects in the TRESIBA and 11.5% Insulin glargine arms for whom data was missing at the time of the HbA_1c measurement.

In Study B, there were 6.3% of subjects in the TRESIBA and 9.8% Insulin detemir arms for whom data was missing at the time of the HbA_1c measurement.

Study C: TRESIBA Administered at the Same Time Each Day or at Any Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients

The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 493 patients with type 1 diabetes mellitus. Patients were randomized to TRESIBA injected once-daily at the same time each day (with the main evening meal), to TRESIBA injected once daily at any time each day or to insulin glargine U-100 injected once-daily according to the approved labeling. The any time each day TRESIBA arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses). TRESIBA in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday. Insulin aspart was administered before each meal in all treatment arms.

The mean age of the trial population was 43.7 years and mean duration of diabetes was 18.5 years. 57.6% were male. 97.6% were White, 1.8% Black or African American. 3.4% were Hispanic. 7.4% of patients had eGFR<60 mL/min/1.73m². The mean BMI was approximately 26.7 kg/m².

At week 26, the difference in HbA_1c reduction from baseline between TRESIBA administered at alternating times and insulin glargine U-100 was 0.17% with a 95% confidence interval of [0.04%; 0.30%] and met the pre-specified non-inferiority margin (0.4%). See Table 7.

Table 7: Results at Week 26 in a Trial Comparing TRESIBA Dosed Once Daily at the Same and at Alternating Times Each Day to Insulin Glargine U-100 in Adult Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes

	TRESIBA at the same time each day + Insulin aspart	TRESIBA at alternating times + Insulin aspart	Insulin glargine U-100 + Insulin aspart
N	165	164	164
HbA1c (%)
Baseline	7.7	7.7	7.7
End of trial	7.3	7.3	7.1
Adjusted mean change from baseline*	-0.41	-0.40	-0.57
Estimated treatment difference [95%CI] TRESIBA alternating — Insulin glargine U-100		0.17 [0.04;0.30]
Proportion Achieving HbA1c < 7% at Trial End	37.0%	37.2%	40.9%
FPG (mg/dL)
Baseline	179	173	175
End of trial	133	149	151
Adjusted mean change from baseline	-41.8	-24.7	-23.9
Daily basal insulin dose
Baseline mean	28 U	29 U	29 U
Mean dose at end of study	32 U	36 U	35 U
Daily bolus insulin dose
Baseline mean	29 U	33 U	32 U
Mean dose at end of study	27 U	30 U	35 U

^* The change from baseline to end of treatment visit in HbA_1c was analyzed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA_1c as covariates.

In Study C, there were 15.8% and 15.9% of subjects in the TRESIBA (same time and alternating times respectively) and 7.9% Insulin glargine arms for whom data was missing at the time of the HbA_1c measurement.