OBJECTIVELY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union-and US-approved versions of IGlar. RESEARCH DESIGN AND METHODSThese were three single-site, randomized, double-blind, two-treatment, fourperiod, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ‡7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTSA total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [C max ]) and PD (maximum glucose infusion rate [R max ]; total glucose infusion during the clamp [G tot ]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80-1.25. Adverse events were similar between treatments. CONCLUSIONSThese studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.

Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog®, IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, open‐label, 2‐sequence, 4‐period crossover, randomized, 8‐hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration‐versus‐time curve from time zero to the time of the last measurable concentration (AUC0–tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter‐ and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20‐U single doses, and PD responses were comparable between formulation strengths.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Exenatide, a treatment for type 2 diabetes, slows gastric emptying as part of its pharmacologic action and may alter the absorption of concomitant oral drugs. This open-label, 2-period, fixed-sequence study evaluated the influence of exenatide coadministration on the pharmacokinetics and pharmacodynamics of warfarin, a narrow therapeutic index drug, in healthy men (N = 16). A single, 25-mg oral dose of warfarin, with a standardized breakfast, was administered alone in period 1 and concomitantly with 10 microg exenatide subcutaneous twice daily in period 2. Exenatide did not produce significant changes in R- or S-warfarin pharmacokinetics. Although there were minor reductions in warfarin anticoagulant effect, the ratios of geometric means for the area under the international normalized ratio (INR)-time curve from dosing until the time of the last measurable INR value or maximum-observed INR response being 0.94 (0.93-0.96) and 0.88 (0.84-0.92), respectively, the magnitude and direction of these changes do not suggest a safety concern from this interaction.