OBJECTIVETo characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units·mL 21 (Gla-300), compared with insulin glargine 100 units·mL 21 (Gla-100) at steady state in people with type 1 diabetes. RESEARCH DESIGN AND METHODSA randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steadystate study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units·kg 21 (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units·kg 21 Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units·kg 21 of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h. RESULTSAt steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (£105 mg·dL 21 ) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100. CONCLUSIONSGla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.Although insulin analog-based products do not exactly replicate dynamic natural portal insulin release, their insulin concentration (INS) profiles closely mimic those of interprandial endogenous insulin levels. However, meeting glycemic goals with oncedaily injections of these agents, while minimizing the frequency of hypoglycemia and

AimsTo characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM).MethodsA total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability.ResultsThe cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15–21] and 33.4% (95% CI 28–41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.ConclusionsGla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.

Insulin glargine is processed in vivo into soluble 21A-Gly-human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub-study compared metabolism and metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla-300) with insulin glargine 100 U/ml (Gla-100, Lantus®, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla-300 (n = 12), and 0.4 U/kg Gla-100 (n = 30) once daily in randomized order for 8 days prior to a 36-h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC-MS/MS). Glargine metabolism was the same regardless of Gla-100 or Gla-300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla-100, and 4 days for Gla-300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla-300 administration compared with M1 profiles after Gla-100.

Recently adopted regulatory standards on infant and follow-on formula for the European Union stipulate that from February 2020 onwards, all such products marketed in the European Union must contain 20–50 mg omega-3 DHA (22:6n–3) per 100 kcal, which is equivalent to about 0.5–1% of fatty acids (FAs) and thus higher than typically found in human milk and current infant formula products, without the need to also include ω-6 arachidonic acid (AA; 20:4n–6). This novel concept of infant formula composition has given rise to concern and controversy because there is no accountable evidence on its suitability and safety in healthy infants. Therefore, international experts in the field of infant nutrition were invited to review the state of scientific research on DHA and AA, and to discuss the questions arising from the new European regulatory standards. Based on the available information, we recommend that infant and follow-on formula should provide both DHA and AA. The DHA should equal at least the mean content in human milk globally (0.3% of FAs) but preferably reach 0.5% of FAs. Although optimal AA intake amounts remain to be defined, we strongly recommend that AA should be provided along with DHA. At amounts of DHA in infant formula up to ∼0.64%, AA contents should at least equal the DHA contents. Further well-designed clinical studies should evaluate the optimal intakes of DHA and AA in infants at different ages based on relevant outcomes.

The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU-approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product.