Biotransformation of insulin glargine after subcutaneous injection in healthy subjects.

OBJECTIVE: It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin. This study examined the primary metabolic degradation products of insulin glargine (LANTUS) in humans. DESIGN: In this single dose, open-label study, insulin glargine was administered subcutaneously at a dose of 0.6 IU/kg; placebo was administered to one control subject. PATIENTS: Four healthy male subjects, plus one control subject, aged 18-50 years were enrolled in this study. MEASUREMENTS: Following insulin glargine administration, blood glucose levels were clamped at the subjects' fasting concentration for 6 h and the amount of 20% glucose infused to maintain this baseline concentration was recorded. Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay (RIA). Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels. The primary pharmacodynamic measure was the glucose infusion rate (GIR). Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject. RESULTS: Metabolic profiling revealed a clear pattern: insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain, to yield products M1 and M2, which are both structurally similar to human insulin. These degradation products are present both at the injection site and in plasma. CONCLUSION: Thus, during treatment with a subcutaneous injection of insulin glargine, metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system.

Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion.

The absolute glucose disposal of insulin glargine (Lantus) was compared to that of regular human insulin in healthy subjects (n=20) using the euglycaemic clamp technique in a single-dose, double-blind, randomized, two-way crossover design. Subjects received 30-minute intravenous infusions of insulin glargine (0.1 IU/kg) or human insulin (0.1 IU/kg) and a 20% glucose solution infused at a variable rate to maintain euglycaemia at the subject's baseline glucose level. At equal baseline blood glucose levels (4.42 mmol/l [range, 4.00-5.16 mmol/l] and 4.42 mmol/l [range, 4.01-4.94 mmol/l], respectively), the area under the glucose infusion rate (GIR) time curves from 0-6 hours (AUC(0-6h)) was within the bioequivalence range (insulin glargine, 663.92 mg/kg; human insulin, 734.85 mg/kg). Both the time to maximum GIR and the suppression of serum C-peptide were similar with insulin glargine and human insulin. The resulting maximum serum insulin concentrations (Cmax) were 151.16 microIU/ml and 202.23 microIU/ml, and the time to Cmax (Tmax) was 30 minutes (the duration of the infusion). The observed differences in the Cmax (the mean value for insulin glargine was about 25% lower than that of human insulin) could be explained by lower cross-reactivity of insulin glargine in the human insulin radioimmunoassay. The employed intravenous route, though definitely not the intended clinical use of insulin glargine, provided the clinical evidence in healthy subjects that on a molar basis insulin glargine is equipotent to regular human insulin regarding glucose disposal.

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique.

AIMS/HYPOTHESIS: This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique. METHODS: In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments. RESULTS: In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC0-24 h) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported. CONCLUSIONS/INTERPRETATION: Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.

Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers.

BACKGROUND: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. METHODS: Twelve young (18-40 years) and 12 elderly (>65 years and

Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus.

OBJECTIVE: To compare the effects of Humalog Mix25 (Humalog Mix75/25 in the USA) (Mix25) and human insulin 30/70 (30/70) on the 24-hour inpatient plasma glucose (PG) profile in patients with type 2 diabetes mellitus (T2DM). DESIGN: A randomised, open-label, 8-week crossover study. Study insulins were injected twice daily, 5 minutes before breakfast and dinner. SETTING: Four-week outpatient (dose-adjustment) treatment phase, and 3-day inpatient (test) phase. PATIENTS: Twenty-five insulin-treated patients with T2DM (ages 40-66 years), mean (+/- standard error of the mean) (SEM) HbA1c 7.7% +/- 0.23%, and body mass index (BMI) 29.3 +/- 0.83 kg/m2. OUTCOME MEASURES: 24-hour PG profiles, PG excursions after meals, PG area under the curve (AUC), and 30-day hypoglycaemia rate. RESULTS: The 2-hour PG excursions following breakfast (5.5 +/- 0.34 v. 7.2 +/- 0.34 mmol/l, p = 0.002) and dinner (2.4 +/- 0.27 v. 3.4 +/- 0.27 mmol/l, p = 0.018) were smaller with Mix25 than with 30/70. PG AUC between breakfast and lunch was smaller with Mix25 than with 30/70 (77.6 +/- 3.8 v. 89.5 +/- 4.3 mmol/h/ml, p = 0.001). PG AUC between lunch and dinner, dinner and bedtime, and bedtime and breakfast did not differ between treatments. Pre-meal and nocturnal PG were comparable. The postprandial insulin requirement for lunch meals was supplied equally by the two insulin treatments. The thirty-day hypoglycaemia rate was low (Mix25 0.049 +/- 0.018 v. 30/70 0.100 +/- 0.018 episodes/patient/30 days, p = 0.586) for both treatments. CONCLUSION: In patients with T2DM, Mix25 improved the 24-hour PG profile with lower postprandial PG excursions than with human insulin 30/70.

The effect of fasting on total serum bilirubin concentrations.

Thirty-seven healthy volunteers, 19 of whom had consistently elevated total serum bilirubin (TSB) concentrations, took part in an open, randomised cross-over study to determine the effect of fasting on TSB concentrations. The study comprised of two treatments. During one treatment period volunteers ate a standard supper but fasted for 24 h thereafter. During the other treatment period volunteers ate a standard supper, snacks, breakfast and lunch. TSB concentrations were measured at regular intervals. In both the normal and high bilirubin groups, minimum TSB values were recorded 4 h after the supper. A 24 h fast more than doubled TSB concentration from baseline values in both the normal and high bilirubin groups. A clinically relevant rise in TSB took place after 12 h into the fasting period (TSB of 17.3 mumol l-1 in the fasted group vs 14.0 mumol l-1 in the non-fasted group). When designing a clinical trial, selecting volunteers, or judging the tolerance of a new drug, the rise in TSB caused by fasting must therefore be taken into account, particularly in trials where volunteers or patients fast before entering the study.

Lack of interaction between ramipril and simvastatin.

Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml-1, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml-1. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.