Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

Helle Linnebjerg; Eric Chen Quin Lam; Mary E. Seger; David Coutant; Laiyi Chua; Chew Lan Chong; Maria M. Ferreira; Danny Soon; Xin Zhang

doi:10.2337/dc14-2623

Special Article Collection: Insulin

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

Helle Linnebjerg¹ ⇑,
Eric Chen Quin Lam²,
Mary E. Seger¹,
David Coutant¹,
Laiyi Chua²,
Chew Lan Chong²,
Maria M. Ferreira³,
Danny Soon² and
Xin Zhang¹

¹Eli Lilly and Company, Indianapolis, IN
²Lilly-NUS Centre for Clinical Pharmacology, Singapore
³PAREXEL International Bloemfontein Early Phase Unit, Bloemfontein, South Africa

Corresponding author: Helle Linnebjerg, linnebjerg_helle{at}lilly.com.

Diabetes Care 2015 Dec; 38(12): 2226-2233. https://doi.org/10.2337/dc14-2623

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Figure 1
Study design. Schematic of study design for all three studies. The test and reference treatments for each study were LY IGlar vs. EU-approved IGlar, LY IGlar vs. US-approved IGlar, and EU-approved IGlar vs. US-approved IGlar, respectively. *Including collection of serial blood samples for pharmacokinetic and pharmacodynamic assessments. R, reference treatment; T, test treatment.
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Figure 2
Mean ± SD C-peptide–corrected serum insulin concentrations and GIRs after administration of 0.5 units/kg s.c. LY IGlar, EU-approved IGlar, or US-approved IGlar in three 2-treatment, 4-period, crossover design studies. A, C, and E: Plots of mean C-peptide–corrected insulin (LY IGlar or IGlar [Lantus]) concentration in the 24 h after 0.5 units/kg s.c. administration of three insulin glargine products. (A, C, and E are from 3 separate studies conducted in separate groups of subjects.) B, D, and F: Plots of mean glucose infusion rate, a measure of insulin action, in the 24 h after 0.5 units/kg s.c. administration of 3 insulin glargine products. (B, D, and F are from 3 separate studies conducted in separate groups of subjects.)

Tables

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Table 1

Subject demographics

Demographics	Study
Demographics	LY IGlar vs. EU-approved IGlar (N = 80)	LY IGlar vs. US-approved IGlar (N = 91)	EU-approved IGlar vs. US-approved IGlar (N = 40)
Male/female (%)	70.0/30.0	93.4/6.6	82.5/17.5
Race (%)	80.0 white, 12.5 black, 7.5 multiple	98.9 Asian, 1.1 white	95.0 Asian, 5.0 white
Age (years)	32.0 ± 10.9	32.7 ± 9.0	31.9 ± 9.9
Weight (kg)	74.8 ± 12.5	70.2 ± 10.3	67.8 ± 9.4
BMI (kg/m²)	24.9 ± 3.2	24.1 ± 2.8	23.8 ± 2.4

Data are means ± SD unless otherwise indicated. N, number of subjects.

Table 2

Comparison of the primary pharmacokinetic and pharmacodynamic parameters of LY IGlar, EU-approved IGlar, and US-approved IGlar in three 2-treatment, four-period, crossover design studies

Treatment (0.5 units/kg)	N (n)	Geometric mean (CV%)^*	Ratio of LS geometric means (test^†/reference) (90% CI)^‡
Statistical analysis of pharmacokinetic parameters
AUC[0–24] (pmol ⋅ h/L)
LY IGlar^†	87 (165)	1,720 (42)	0.90 (0.86, 0.94)
US IGlar	89 (167)	1,900 (35)
LY IGlar^†	79 (156)	1,810 (40)	0.91 (0.87, 0.96)
EU IGlar	80 (157)	1,980 (36)
EU IGlar^†	40 (75)	2,000 (35)	0.98 (0.91, 1.05)
US IGlar	40 (76)	2,060 (39)
C_max (pmol/L)
LY IGlar^†	88 (167)	103 (41)	0.92 (0.87, 0.96)
US IGlar	89 (169)	111 (34)
LY IGlar^†	80 (158)	112 (39)	0.95 (0.90, 1.00)
EU IGlar	80 (158)	119 (34)
EU IGlar^†	40 (76)	120 (33)	0.99 (0.92, 1.06)
US IGlar	40 (77)	122 (37)
t_max (h)^§
LY IGlar^†	88	12.00	0.50 (−0.76, 1.25)
US IGlar	89	12.00
LY IGlar^†	80	12.00	0.00 (−0.75, 0.75)
EU IGlar	80	13.50
EU IGlar^†	40	12.00	−0.75 (−1.50, 0.50)
US IGlar	40	12.00
Statistical analysis of pharmacodynamic parameters
G_tot (mg/kg)
LY IGlar^†	88 (171)	1,670 (60)	0.91 (0.85, 0.98)
US IGlar	88 (170)	1,820 (74)
LY IGlar^†	80 (158)	2,580 (45)	0.95 (0.91, 1.00)
EU IGlar	80 (158)	2,710 (40)
EU IGlar^†	40 (76)	1,870 (84)	1.00 (0.89, 1.13)
US IGlar	40 (77)	1,880 (77)
R_max (mg/kg/min)
LY IGlar^†	88 (171)	2.12 (54)	0.93 (0.88, 0.98)
US IGlar	88 (170)	2.27 (58)
LY IGlar^†	80 (158)	2.85 (46)	0.99 (0.94, 1.04)
EU IGlar	80 (158)	2.88 (41)
EU IGlar^†	40 (76)	2.35 (67)	0.97 (0.88, 1.07)
US IGlar	40 (77)	2.44 (63)

n, number of observations; N = number of subjects.
↵*Summary statistics of pharmacokinetic and pharmacodynamic parameters; does not reflect results of the statistical analysis.
↵†The test treatment in each comparison.
↵‡Statistical model: log(parameter) = period + sequence + treatment + error, subject (random), period sequence treatment (categorical).
↵§Median or median difference (95% CI) are presented for t_max. t_max was analyzed using a nonparametric approach based on the Hodges-Lehmann method. Analysis was based on subject's t_max values averaged across the 2 occasions where the same treatment was administered, if applicable.