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What is already known about this subject • Nonclinical studies have shown that exenatide is primarily cleared by the renal system. • It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI). What this study adds • Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide. • However, exenatide is not recommended in patients with severe RI or end‐stage renal disease. Aims To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). Methods Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end‐stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single‐dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. Results Mean half‐life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.). Conclusions Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.

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.

OBJECTIVEHuman regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL).RESEARCH DESIGN AND METHODSThis was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects.RESULTSBoth overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05).CONCLUSIONSOverall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

OBJECTIVEWe evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODSThis was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m 2 /min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-3 H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTSMean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONSThe novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.In vivo, insulin is secreted from pancreatic b-cells and enters the circulation via the portal vein, where on first pass the liver extracts ;40-80% (1-7). As a result, systemic circulating insulin levels are reduced compared with those in the portal vein, and subsequent insulin action in the peripheral target tissues is also reduced compared with the liver. Consequently, the relative ratio of hepatic action to peripheral action ranges between 2:1 and 4:1 (1,2,4,8-10). In contrast, when exogenous insulin is administered peripherally, insulin is distributed equally across the liver and peripheral tissues (11,12) and thus does not mimic normal physiology.

Background Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog ® in patients with type 1 diabetes mellitus (T1DM). Methods This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Results Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. Conclusion In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

Aims To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D). Materials and Methods This was a randomized, double‐blind, four‐period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. Results URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half‐maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post‐meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post‐meal with URLi were comparable to those in healthy subjects. Conclusions URLi demonstrated the fastest insulin absorption and the greatest numeric PPG‐lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

Abstract. This randomized, placebo-controlled, double-blind, parallel study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly (QW) in 30 japanese patients with type 2 diabetes (T2d) suboptimally controlled by diet and exercise alone or combined with biguanide, sulfonylurea, thiazolidinedione, or combinations of these agents (58.6% male; 58±9 years; body mass index 26.3±2.9 kg/m 2 ; hemoglobin a 1c [Hba 1c ] 7.4±0.8%; fasting plasma glucose [FPG] 156.1±29.1 mg/dL; duration of T2d 6±5 years; means ± sd). Patients were randomized in a 1:1:1 ratio to subcutaneous placebo QW, exenatide QW 0.8 mg, or exenatide QW 2.0 mg for 10 weeks. all evaluable patients were analyzed (placebo QW, n=10; exenatide QW 0.8 mg, n=10; exenatide QW 2.0 mg, n=9), unless otherwise stated. steady-state plasma exenatide concentrations were observed by Week 8 of the study. For the evaluable pharmacokinetic population, geometric mean (90% confidence interval) steady-state plasma concentrations (pg/mL) were 81.2 (68.3-96.4) and 344.5 (256.5-462.7) with exenatide QW 0.8 mg (n=8) and exenatide QW 2.0 mg (n=5), respectively. Baseline-to-Week 10 glycemic improvements with placebo QW, exenatide QW 0.8 mg, and exenatide QW 2.0 mg, respectively, were: Hba 1c (%): -0.4±0.3, -1.0±0.7, and -1.5±0.7; FPG (mg/dL): -20.5±20.4, -25.2±10.9, and -50.8±27.8; and 2-hour postprandial plasma glucose excursions (mg/dL): -8.8±26.9, -50.0±41.1, and -59.7±26.8 (means ± sd). No serious adverse events (aEs) were reported and no aEs led to study discontinuation in any group. The most frequent aE observed was mild-to-moderate injection site induration. No serious hypoglycemia was reported. Exenatide QW for 10 weeks was well tolerated and improved short-term glycemic control in japanese patients with suboptimally controlled T2d.