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These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935].

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.

Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.

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.

In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.

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.

After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.