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HUMULIN® R U-500 (insulin human injection): Pharmacokinetics and Pharmacodynamics Clinical Experience

The time action characteristics reflect both prandial and basal activity attributed to the high concentration of Humulin R U-500.

Detailed Information

The prandial and basal activity of U-500R is consistent with clinical experience (Table 1. Pharmacokinetic and Pharmacodynamic Data From U-500R and U-100R Studies).1-3

Table 1. Pharmacokinetic and Pharmacodynamic Data From U-500R and U-100R Studies

Study Design


Randomized, double-blind, single-site, crossover, euglycemic clamp study including 24 healthy subjects who were

  • obese: BMI = 34.4 ± 2.6 kg/m2,a and

  • aged: 21 to 65 years old.1

Evaluated PK/PD of U-500R and U-100R administered as single SC doses of

  • 50 units, and

  • 100 units.

Primary objective was relative exposure (AUC0-t’) for U-500R and U-100R.

Secondary objectives included

  • PK/PD parameters comparison between the 2 formulations and doses

  • safety, and

  • tolerability.

Similar between U-100R and U-500R at both doses were

  • relative exposure, and

  • overall effect: total glucose infused during a clamp

Significantly lower for U-500R at both doses were

  • peak insulin concentration, and

  • peak effect.

Significantly longer for U-500R vs U-100R at both doses was

  • duration of action.

Significantly longer for U-500R at only the 100-unit dose were

  • time to peak concentration, and

  • time to peak effect.

Authors concluded

  • dosing 30 minutes before the meal is likely appropriate for U-500R as recommended for U-100R

  • U-500R as insulin monotherapy may be a reasonable treatment option for obese patients with T2DM due to the longer duration of effect, and

  • precautions should be taken to monitor for and avoid hypoglycemia, particularly at night with the use of U-500R.

No severe TEAE reported.

No discontinuation due to AE.

AEs reported included

  • 12 headache, and

  • 2 nausea.

Simulation modeling PK/PD study with U-500R derived from 3

  • single-dose

  • crossover

  • euglycemic clamp studies.2

Evaluated PK/PD of single dose U-500R in

  • 46 healthy obese subjects

  • 18 healthy normal BW subjects, and

  • 30 T1DM normal BW patients.

Insulin doses:

  • healthy obese:

    • 0.4 to 0.6 units/kg (50 units), or

    • 0.8 to 1.3 units/kg (100 units)

  • healthy normal BW:

    • 0.05 to 0.4 units/kg

  • T1DM normal BW:

    • 0.1 to 0.2 units/kg (12 units)

Simulation profiles:

  • once-daily, single doses of 165, 250, 500, and 750 units and at steady-state ~500 unit dose at 7 AM

  • twice-daily, steady state doses of 300, and 200 units at 7 AM and 6 PM, and

  • thrice-daily, steady-state doses of 200, 150, and 150 units at 7 AM, noon, and 6 PM

All 3 dosing regimens achieved steady-state PK by 24 hours postdose.

  • Once-daily regimen showed greatest fluctuation in the PK/PD parameters

    • peak insulin concentration

    • effect 5 and 7 hours after dosing, and

    • substantial decrease in insulin effects in the evening hours.

  • Twice-daily regimen showed

    • gradual increase in insulin concentration, and

    • effects with each dose and a stable basal effect.

  •  Thrice-daily regimen showed

    • sustained effects between doses

    • less pronounced postdose PD effects, and

    • marginally better PD effects throughout the entire day.b

The PK/PD simulation modeling indicated that the steady-state basal PD effect from both twice-daily and thrice-daily dosing of U 500R seems to negate the need for concurrent U-100R basal insulin.

Randomized, prospective, open label, multicenter, 24-week study, including 325 patients with T2DM taking > 200 units of insulin/day.3

Compared the efficacy and safety of U-500R dosed

  • thrice-daily, and

  • twice-daily.

Mean baseline demographics were

  • age: 55.4 ± 9.8 years

  • BMI: 41.9 ± 7.5 kg/m2

  • HbA1c: 8.7% ± 1%

  • T2DM duration: 15.2 ± 7.4 years

  • TDI: 287.5 ± 80.5 units/day or 2.4 ± 0.8 units/kg/day

  • number of daily injections: 4.8 ± 1.3 of U-100R

Primary objective was HbA1c change.c

Secondary objective was 7 point SMPG profiles.

Hypoglycemia definitions were

  • documented symptomatic: PG ≤ 70 mg/dL and ≥ 1 sign/symptom indicative of hypoglycemia

  • nocturnal: documented symptomatic between bedtime and waking, and

  • severe: documented symptomatic requiring third-party assistance.

HbA1c change: LSM = 0.10% (95% CI, -0.33 to 0.12%), supporting clinical equivalence between the 2 dosing regimensd

HbA1c reductions significant (p<.001) for both groups were

  • 1.22% for twice-daily dosing regimen, and

  • 1.12%  for thrice-daily dosing regimen. 

7 point SMPG profiles difference between groups were

  • not significant at randomization, and

  • not significant at week 24.

Thrice-daily dosing resulted in a significantly lower incidence and rate of documented symptomatic hypoglycemia than twice-daily dosing

No difference in the incidence or rate of severe hypoglycemia groups

The prandial/basal time-concentration/action characteristics of U-500R provide explanation for the differences between the groups in

  • nonsevere hypoglycemia rates

  • timing of hypoglycemic events

  • timing of non-severe hypoglycemia, and

  • differing rates of non-severe hypoglycemia.

Higher rate of hypoglycemia in

  • twice-daily group at noon correlated with

    • 60% TDI at breakfast

  • thrice-daily group at dinner correlated with

    • 40% TDI at breakfast, and

    • 30% TDI at lunch.

Abbreviations: AE = adverse events; AUC0-t’ = area under the serum insulin concentration vs time curve from zero to return to baseline; BMI = body mass index; BW = body weight; HbA1c = glycated hemoglobin; LSM = least squares mean; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SC = subcutaneous injection; SMPG = self-monitored plasma glucose; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TDI = total daily insulin; TEAE = treatment-emergent adverse event; U-100R = Humulin® R U-100 (regular insulin human injection) 100 units/mL; U-500R = Humulin R U-500 (insulin human injection) 500 units/mL.

a Mean value

b Compared with twice-daily dosing.

c From baseline

d Prespecified noninferiority margin of 0.4%


Enclosed Prescribing Information

HUMULIN® R U-100 (insulin human injection), for subcutaneous or intravenous use, Lilly

HUMULIN® R U-500 (insulin human injection), for subcutaneous use, Lilly


The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1. de la Peña A, Riddle M, Marrow LA, et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects. Diabetes Care. 2011;34(12):2496-2501.

2. de la Peña A, Ma X, Reddy S, et al. Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin. J Diabetes Sci Technol. 2014;8(4):821-829.

3. Hood RC, Arakaki RF, Wysham C, et al. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: a randomized, titration-to-target clinical trial. Endocr Pract. 2015;21(7):782-793.


U-500R = Humulin® R U-500 (insulin human injection) 500 units/mL

Date of Last Review: April 16, 2018

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