This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, ...randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-C
), area under the plasma insulin concentration-time curve to the last quantifiable concentration (INS-AUC
), area under the GIR-time curve during the clamp (GIR-AUC
), and maximum GIR (GIR
). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval CI 0.94-1.05) for INS-C
and 1.02 (90% CI 1.00-1.04) for INS-AUC
. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93-1.06) for GIR-AUC
and 1.01 (95% CI 0.95-1.08) for GIR
. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80-1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.
The fluorogenic substrate 6,8-difluoro-4-methylumbiliferyl phosphate (DIFMUP) has been widely used for the detection of serine and threonine phosphatase activities. Here we describe the use of this ...substrate for the characterization of protein tyrosine phosphatases (PTPs) and for the screening for PTP inhibitors. The measured kinetic and inhibitor constants for DIFMUP cleavage were comparable with those of the widely used but less discriminative and practicable substrates,
para-nitrophenylphosphate and phosphotyrosine-containing peptides, respectively. Furthermore, the continuous and highly sensitive assay allows fast and accurate investigations of the type, kinetic behavior, and binding mode of small-molecule inhibitors. We discuss the validation of this assay system for various PTPs and its use in inhibitor screening for PTP1B.
Aim
To compare the pharmacokinetic exposure of SAR341402 Mix 70/30 (SARAsp‐Mix) with US‐ and European (EU)‐approved versions of insulin aspart Mix 70/30 (NovoLog Mix 70/30 NN‐Mix‐US/NovoMix 30 ...NN‐Mix‐EU) and SAR341402 insulin aspart solution (SAR‐Asp) in subjects with type 1 diabetes.
Materials and Methods
This was a randomized, double‐blind, crossover trial in two cohorts. Fifty‐two subjects received a single subcutaneous 0.3 U/kg dose of each treatment and underwent a euglycaemic clamp procedure lasting for a maximum of 24 hours after dosing. In cohort 1, subjects (N = 36) were exposed once each to SARAsp‐Mix, NN‐Mix‐US and NN‐Mix‐EU. In cohort 2, subjects (N = 16) were exposed once each to SARAsp‐Mix and SAR‐Asp.
Results
Of the 52 subjects randomized, 48 completed all treatment periods. In cohort 1, the extent of exposure (total and maximum concentration) was similar among the three treatments, with the 90% confidence intervals for pairwise treatment ratios meeting the predefined acceptance range (0.80 to 1.25). In cohort 2, statistically significant differences (P < .001) in early (0‐4 hours) and intermediate (4‐12 hours) exposure to SARAsp‐Mix compared with SAR‐Asp were observed, all exceeding a 20% difference. Pharmacodynamic results were in support of the pharmacokinetic findings for both cohorts. All treatments were well tolerated and there were no relevant differences in safety variables among treatments.
Conclusions
SARAsp‐Mix showed similar pharmacokinetic exposure to commercially available insulin aspart Mix 70/30 formulations, and a distinct exposure profile compared with SAR‐Asp.
SAR341402 (SAR-Asp), NovoLog (NN-Asp-US) and NovoRapid (NN-Asp-EU) are rapid-acting insulin aspart products.
Exposure (PK) to and activity (PD) of SAR-Asp (T) NN-Asp-US (R1) and NN-Asp-EU (R2) were ...compared in a single-center, randomized, double-blind, 3-treatment, 3-period, crossover, euglycemic clamp study. Thirty male T1D subjects (22-59 years) were randomized to receive 0.3 U/kg T, R1 and R2 in separate periods; 29 subjects completed all 3 treatment periods. PK and PD (Glucose Infusion Rate, GIR) by euglycemic clamp were assessed up to 12 hours.
Mean concentration and body weight standardized GIR vs. time profiles for T, R1 and R2 were similar. Exposure to and activity of T, R1 and R2 were similar between treatments, as the 90% CIs for the treatment ratios for the primary and main secondary PK and PD endpoints were within the predefined acceptance range (0.80-1.25) (Table). Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for T, R1 and R2. No safety concerns were noted in laboratory, vital signs, or ECG data.
In summary, this study demonstrated similar insulin aspart exposure profiles and PD activity for SAR-Asp to NN-Asp-US and NN-Asp-EU and between NN-Asp-US and NN-Asp-EU, rendering SAR-Asp a biosimilar/follow-on product.
Disclosure
C. Kapitza: Research Support; Self; ADOCIA, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Mylan, Nestlé, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi-Aventis, Wockhardt, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. L. Nosek: None. A. Lehmann: Employee; Self; Sanofi-Aventis Deutschland GmbH. W. Schmider: Employee; Self; Sanofi. B. Rotthaeuser: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. I.K. Nowotny: Employee; Self; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Self; Sanofi.
Funding
Sanofi
Objective: The LixiLan clinical trials of insulin glargine (iGlar)/lixisenatide fixed-ratio combination (iGlarLixi) investigated the safety and efficacy of iGlarLixi versus iGlar: LixiLan-O ...(NCT02058147) in patients with type 2 diabetes (T2D) inadequately controlled on oral antidiabetes drugs (OADs) and LixiLan-L (NCT02058160) in patients with T2D inadequately controlled on basal insulin ± OADs. In these two trials, both iGlar and iGlarLixi were titrated to a maximum (capped) dose of 60 units. We evaluated whether this may have affected the reported glycemic efficacy of iGlar, and the glycemic differences observed between treatment with iGlarLixi and iGlar.
Methods: The efficacy of iGlar under uncapped conditions was simulated in a two-step approach. First, a model characterizing the relationship between iGlar dose and fasting self-measured plasma glucose (f-SMPG) was developed. Then, the relationship between glycated hemoglobin A1
c
(A1C) and f-SMPG was established to translate simulated f-SMPG responses to A1C responses.
Results: Most patients achieved stable f-SMPG at ∼60 units/day, with no further reduction with increasing insulin dose. In comparisons of observed/capped and simulated/uncapped changes in mean A1C from baseline to Week 30, iGlarLixi consistently demonstrated treatment benefit compared with iGlar. Uncapping resulted in a slightly higher mean iGlar dose in both LixiLan-O (+0.72 units) and LixiLan-L (+2.1 units), without marked impact on f-SMPG or A1C change from baseline.
Conclusion: Uncapping the iGlar dose in LixiLan-O and LixiLan-L would not have led to significant improvements in mean A1C reduction in the iGlar arm, supporting the conclusion that iGlarLixi provides additional, clinically relevant glycemic control versus iGlar alone.
Introduction
The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 ...diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10 μg and 30 U/15 μg) doses following single subcutaneous administration in healthy Chinese participants.
Methods
This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10 μg) or 2:1 (30 U/15 μg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15 μg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10 μg and iGlarLixi 30 U/15 μg). Safety and tolerability were also assessed.
Results
In iGlarLixi 30 U/15 μg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-
t
max
was 14.00 h for iGlar and 13.00 h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median
t
max
of 3.25 and 2.00 h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide.
Conclusion
iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions.
Trial registration
U1111-1194-9411.
Objective: To evaluate the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen (5-20 µg), alone or in fixed-ratio combination with insulin glargine (iGlar; iGlarLixi).
Methods: Data from ...three clinical studies were analyzed to assess lixisenatide efficacy and safety: a phase 2a trial assessing gastric emptying effects (ACT6011); a phase 2b dose-ranging trial (DRI6012); and a randomized controlled phase 3 trial comparing iGlarLixi with its components of iGlar and lixisenatide (LixiLan-O). Efficacy metrics included glycated hemoglobin A
1c
(A1C), post-prandial glucose (PPG) values following a standardized breakfast, fasting plasma glucose (FPG), and weight change. Occurrence of gastrointestinal adverse events was also assessed.
Results: ACT6011: lixisenatide doses from 5-20 μg once daily (QD) suppressed PPG; maximal reductions in mean PPG area under the curve were achieved with doses ≥12.5 µg QD, but doses as low as 5 μg achieved 44% of maximal reduction. DRI6012: lixisenatide doses 5-20 μg QD resulted in significant, dose-dependent decreases in A1C, percentage of patients achieving A1C <7.0%, and 2-h PPG levels; doses of 20 μg achieved complete suppression of PPG. LixiLan-O: iGlarLixi decreased 2-h PPG across the entire dose range. Lixisenatide dose was unrelated to reductions in FPG with iGlarLixi. Similar reductions in A1C were seen with iGlarLixi across all lixisenatide doses.
Conclusions: This analysis demonstrates the clinical benefit of lixisenatide alone or in the formulation of iGlarLixi over the entire dose range of lixisenatide contained in iGlarLixi (5-20 µg), supporting the selection of the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen.
Trial registration:
ClinicalTrials.gov identifier: NCT00299871.
Aim
To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR‐Asp) and the insulin aspart reference product (NovoLog; NN‐Asp) leads to equivalent pharmacokinetic (PK) ...exposure compared with continuous use of NN‐Asp in adults with type 1 diabetes (T1D).
Materials and Methods
This multicentre, open‐label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once‐daily insulin glargine U100 as basal insulin to four 4‐week periods of alternating multiple daily injections of SAR‐Asp and NN‐Asp (NN‐Asp for the first 4 weeks, SAR‐Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN‐Asp (non‐switching group). At week 16, a single dose (0.15 U/kg) of SAR‐Asp in the switching group (n = 95) or NN‐Asp in the non‐switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax) of SAR‐Asp versus NN‐Asp after the single dose at week 16.
Results
The extent of PK exposure was similar between the two treatments (SAR‐Asp in the switching group and NN‐Asp in the non‐switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8‐1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8‐1.25.
Conclusions
PK exposure of SAR‐Asp (switching group) and reference NN‐Asp (non‐switching group) were similar, supporting interchangeability between these two insulin aspart products.
This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a ...randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.
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