No abstract

No abstract

No abstract

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.

The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.

Aims/hypothesis: The efficacy and safety of human insulin inhalation powder (HIIP) plus insulin glargine were compared to subcutaneously injected insulin (SC insulin) plus insulin glargine in patients with type 1 diabetes. Methods: This was a randomised, open-label crossover study in which one group of patients received preprandial HIIP plus insulin glargine for 12 weeks, followed by the same duration with preprandial SC insulin (lispro or regular) plus insulin glargine. Another group of patients received the reverse treatment sequence. The trial was designed as a non-inferiority comparison of the two treatments for effect on HbA 1c ; blood glucose levels were also monitored. Safety assessments included adverse event reporting and hypoglycaemic events. Results: HbA 1c at endpoint was 7.95±0.12% for the HIIP treatment and 8.06±0.12% for the SC insulin treatment; mean changes from baseline to endpoint were −0.08 and 0.00%, respectively, (p=NS). The upper limit of the 95% CI of mean difference in HbA 1c between the two treatments was 0.02%, indicating that HIIP was not inferior relative to SC insulin, as measured against the pre-defined margin of 0.3%. Fasting blood glucose was significantly lower for HIIP treatment (8.09±0.33 mmol/l; n=117) than for SC insulin treatment (9.05±0.33 mmol/l; n=111) (p=0.01). Safety profiles were comparable between the two treatments. The rate of any hypoglycaemia (least-squares mean adjusted for 30 days±SE) was 8.9±0.7 and 8.2±0.8 for HIIP and SC insulin treatments, respectively, (p=0.29). The rate of nocturnal hypoglycaemia was greater for HIIP (4.2±0.4) than for SC insulin (2.7±0.4; p<0.001). Conclusions/interpretation: HIIP was similar in efficacy to SC insulin for glycaemic control in type 1 diabetes mellitus. The two treatments had comparable safety profiles.

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.

OBJECTIVE -To determine the pharmacokinetic (PK) and glucodynamic (GD) dose response of human insulin inhalation powder (HIIP) delivered via AIR particle technology and dose equivalence to subcutaneous (SC) insulin lispro.RESEARCH DESIGN AND METHODS -Twenty healthy, nonsmoking, male or female subjects (aged 29.6 Ϯ 6.9 years, BMI 23.2 Ϯ 2.3 kg/m 2 , means Ϯ SD) with normal forced vital capacity and forced expiratory volume were enrolled in an open-label, randomized, sevenperiod, euglycemic glucose clamp, cross-over trial. Each subject received up to four single doses of HIIP (2.6, 3.6, 5.2, or 7.8 mg) and three doses of SC lispro (6, 12, or 18 units) from 5 to 18 days apart.RESULTS -HIIP demonstrated a similar rapid onset but an extended time exposure and a prolonged duration of effect (late t 50% 412 vs. 236 min, P Ͻ 0.001) compared with SC lispro. The HIIP versus SC lispro doses of 2.6 mg vs. 6 units, 5.2 mg vs. 12 units, and 7.8 mg vs. 18 units achieved similar PK area under the serum immunoreactive insulin (IRI) concentration-versustime curve from time zero until the serum IRI concentrations returned to the predose baseline value [AUC (0-tЈ) ] and GD (G tot ) responses. The median insulin (t max ) was not different between HIIP and SC lispro (45 min for both), although the median time of return to baseline for PK was apparently longer for HIIP compared with SC lispro (480 vs. 360 min). Relative bioavailability and relative biopotency of HIIP were consistent across doses (8 and 9%).CONCLUSIONS -While the time-action profile was longer for HIIP than for SC lispro, both treatments showed rapid initial absorption and similar overall PK exposure and GD effect. HIIP was as well tolerated as SC lispro, thereby offering a promising alternative to injectable insulin therapy. Diabetes Care 28:2400 -2405, 2005T he disease burden of diabetes continues to grow and currently affects Ͼ18 million Americans and their families (1). Despite increased use of diabetes medications (without, however, increased utilization of insulin), overall diabetes control A1C among individuals diagnosed with diabetes in the U.S. has not improved, with A1C rising from 7.7 to 7.9% during the final decade of the last century (2). These data emphasize a need for alternative diabetes therapies with earlier more physiologic use of insulin.The delivery of insulin by the lung may provide an attractive alternative for many patients with diabetes (3-8). However, alternative insulin delivery systems must meet certain pharmacokinetic (PK) and glucodynamic (GD) requirements to reach maximum utility (9). Specifically, the dose-response characteristics of inhaled insulin should be similar to those of injectable insulins, like human regular insulin or fast-acting insulin analogs such as insulin lispro. Moreover, inhaled insulin should demonstrate satisfactory dose reproducibility; that is, intrasubject variability of inhaled insulin should be similar to or better than that of injectable insulin. Finally, the ratio of dose equivalence between inhaled insulin an...