Maximum Glucose Infusion Rate Research Articles

Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart.

AimsTo evaluate the pharmacokinetics and pharmacodynamics of faster‐acting insulin aspart and insulin aspart in a randomized, single‐centre, double‐blind study.MethodsFifty‐two patients with type 1 diabetes (mean age 40.3 years) received faster‐acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose‐clamp conditions, in a three‐way crossover design (3–12 days washout between dosing).ResultsFaster‐acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5‐fold greater with faster‐acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster‐acting insulin aspart had a significantly greater glucose‐lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUCGIR), 0–30 min ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUCGIR , 0–2 h) was 10% greater for faster‐acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose‐lowering effects, indicating similar overall potency.ConclusionsFaster‐acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose‐lowering effect, with similar potency.

Insulin degludec/insulin aspart produces a dose-proportional glucose-lowering effect in subjects with type 1 diabetes mellitus.

To evaluate the pharmacodynamic dose-response relationship of insulin degludec/insulin aspart (IDegAsp), a novel, soluble co-formulation of the ultra-long-acting basal insulin, insulin degludec (IDeg), with the rapid-acting prandial insulin (IAsp), across different doses in patients with type 1 diabetes (T1DM). This was a randomized, single-centre, double-blind, four-period, incomplete block, crossover trial. A cohort of 33 people with T1DM received single doses (0.4, 0.6 or 0.8 U/kg) of IDegAsp or the comparator, biphasic insulin aspart 30, in a randomized sequence of four treatment periods, each separated by a washout of 13-21 days. Pharmacodynamic response was assessed using a 26-h euglycaemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/l (100 mg/dl). A rapid onset of action and a distinct peak attributable to IAsp was observed in the glucose infusion rate (GIR) profile, followed by a separate, flat and stable basal glucose-lowering effect attributable to the IDeg component. The mean area under the GIR curve over 24 h (AUC(GIR,0-24 h)), and the mean maximum GIR (GIR(max)) increased with increasing dose level of IDegAsp. A dose-response relationship for IDegAsp was demonstrated for AUC(GIR,0-24 h) and GIR(max), indicating dose proportionality. A dose-concentration relationship was also observed for both the basal and bolus components of IDegAsp. IDegAsp has a clear dose-response relationship, indicating the clinical potential for straightforward titration according to individual patient needs.

Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region.

Background and ObjectivesPatients with diabetes mellitus inject insulin in different regions of the body. This study investigated the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a new-generation once-daily basal insulin with an ultra-long duration of action, after subcutaneous (SC) administration in different injection regions.MethodsIn this study, 20 healthy subjects received single SC doses of IDeg (0.4 U/kg; separated by 13–21 days) in the thigh, abdomen and deltoid in a randomised, open-label, single-centre, single-dose, complete crossover trial. Each dose was followed by a 24-h euglycaemic clamp and 120-h pharmacokinetic blood sampling. The obtained pharmacokinetic/pharmacodynamic profiles were extrapolated to steady state by simulation using a pharmacokinetic/pharmacodynamic model.ResultsTotal IDeg exposure [area under the IDeg serum concentration–time curve 0–120 h after a single dose (AUCIDeg,0–120h,SD)] and maximum serum concentration [maximum IDeg serum concentration after a single dose (C max,IDeg,SD)] were higher (6–7 and 23–27 %, respectively) following a single SC dose in the deltoid or abdomen, compared with the thigh, as also observed with other insulin preparations. No statistical difference was observed in these measures between deltoid and abdominal administration. No pronounced differences were observed in the glucose-lowering effect of IDeg [area under the glucose infusion rate (GIR) curve 0–24 h after a single dose (AUCGIR,0–24h,SD) and maximum GIR after a single dose (GIRmax,SD)] when injected in the thigh, abdomen or deltoid (AUCGIR,0–24h,SD 2,572, 2,833 and 2,960 mg/kg, respectively). Simulated mean steady-state pharmacokinetic and pharmacodynamic profiles supported a flat and stable IDeg exposure and effect regardless of injection region, with comparable total glucose-lowering effects [area under the GIR curve at steady state (AUCGIR,τ,SS)] between the thigh, abdomen and deltoid.ConclusionsThese findings support administering IDeg SC in the thigh, upper arm or abdominal wall without affecting IDeg absorption or effect at steady state.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-014-0218-x) contains supplementary material, which is available to authorized users.

Ultra-Long Pharmacokinetic Properties of Insulin Degludec are Comparable in Elderly Subjects and Younger Adults with Type 1 Diabetes Mellitus

BackgroundManagement of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.ObjectiveThe aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.MethodsThis trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18–35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUCIDeg,τ,SS) (τ = 0–24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (Cmax,IDeg,SS). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUCGIR,τ,SS), and the maximum GIR at steady state (GIRmax,IDeg,SS).ResultsTotal exposure (AUCIDeg,τ,SS) and maximum concentration (Cmax,IDeg,SS) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUCIDeg,τ,SS and Cmax,IDeg,SS and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73–1.47) and 1.02 (95 % CI 0.74–1.39), respectively. Mean AUCIDeg,0–12h,SS/AUCIDeg,τ,SS was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUCGIR,τ,SS (the primary endpoint of this study) and GIRmax,IDeg,SS. Estimated mean age group ratios (elderly/younger adult) for AUCGIR,τ,SS and GIRmax,IDeg,SS and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47–1.31) and 0.80 (95 % CI 0.54–1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. ConclusionsThe exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes.Clinical trials.gov number: NCT00964418

A comparison of the pharmacodynamic profiles of insulin detemir and insulin glargine: A single dose clamp study in people with type 2 diabetes

AimThe pharmacodynamic properties of a single dose of 0.5U/kg insulin detemir and insulin glargine were compared during two 24-h isoglycaemic clamps, one week apart. MethodsThe order of treatments was randomised. At approximately 0830h, persons with T2DM received subcutaneous administration of a 0.5U/kg dose of either insulin detemir or insulin glargine into the anterior abdominal wall. Plasma glucose was measured at 10-min intervals throughout the 24-h clamp period and isoglycaemia was maintained by variable infusion of 20% glucose. Glucose infusion rates (GIR) and plasma C-peptide were determined throughout each 24-h period. ResultsEleven persons with type 2 diabetes (8 male) with mean (SD) age 58.5years (8.5), BMI 30.8kg/m2 (2.8) and HbA1c 7.5% (0.6) were studied. Plasma glucose remained constant during the clamp (CV: insulin detemir 3.7%; insulin glargine 3.8%). Following injection of insulin detemir, GIR increased, reaching a mean peak of 2.29mg/kg/min (95% CI 1.64, 2.94) at 11.6h (range 8.9 to 14.3) compared to 1.71mg/kg/min (95% CI 1.4, 2.0) at 10.2h (8.1 to 12.3) for insulin glargine (P=0.025 for GIRmax). Plasma C-peptide decreased during the study period, remaining significantly lower than the fasting level at the study end after both analogues, insulin detemir (P=0.01) and insulin glargine (P=0.02). ConclusionIn persons with T2DM, no difference in duration of action following a single subcutaneous dose of insulin detemir and insulin glargine could be observed. Insulin detemir showed greater between subject variability and achieved a significantly higher maximum GIR than insulin glargine.

Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

OBJECTIVEWe investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo.RESEARCH DESIGN AND METHODSBefore the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide–negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration.RESULTSThe ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08).CONCLUSIONSA dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.

Time–Action Profile of an Oral Enteric Insulin Formulation in Healthy Chinese Volunteers

BackgroundInsulin is an essential treatment for both type 1 and 2 diabetes. Among the available routes of insulin administration, oral delivery is the most appealing option. ObjectiveThe purpose of this study was to evaluate the pharmacodynamic and pharmacokinetic profiles of orally administered enteric insulin and compare the time–action of these oral insulin capsules with neutral protamine Hagedorn (NPH) insulin. MethodsThis was a single-center, randomized, 4-period, crossover study. Twelve healthy volunteers (3 per group) received 1 of 3 doses of oral enteric insulin (50, 100, or 200 U) or 1 subcutaneous injection of NPH insulin (6 U) on 4 separate days. After administration, glucose infusion rates and serum insulin concentrations were monitored for 10 hours. ResultsGlucose infusion rates increased after administration of either NPH or oral enteric insulin. The mean times for maximal metabolic effects for 50, 100, and 200 U of oral enteric insulin were 250 (118), 170 (58), and 236 (132) minutes, respectively, compared with 243 (79) minutes for NPH insulin. The onset of action was slower for oral enteric insulin at 50 U (38 [10] minutes), 100 U (41 [18] minutes), and 200 U (65 [58] minutes) compared with NPH insulin (35 [8] minutes). The maximum glucose infusion rates for oral enteric insulin treatment (1.66 [0.50], 1.61 [1.00], and 1.80 [0.60] mg/kg/min for 50, 100, and 200 U, respectively) were lower compared with NPH insulin (2.06 [0.82] mg/kg/min), although these differences were not statistically significant. ConclusionsOral enteric insulin capsules induced significant glucodynamic effects and exhibited a time–action profile similar to that of NPH insulin in these healthy volunteers. No detectable increases in serum insulin concentration were observed in any treatment group. Trial registry number: ChiCTR-TRC-12001872.

The Alteration of Aspart Insulin Pharmacodynamics When Mixed With Detemir Insulin

OBJECTIVEMixing rapid acting insulin analogs with detemir insulin to minimize daily injections has been adopted as a common regimen, especially for some children with type 1 diabetes, despite the manufacturing company’s caution against mixing these analogs in the same syringe. The effect of this practice on the pharmacodynamics (PD) of rapid-acting insulin has not been widely studied. This crossover, randomized study was undertaken to determine whether mixing aspart with detemir insulin has an adverse effect on the early glucodynamic action of rapid-acting insulin analog in humans.RESEARCH DESIGN AND METHODSEight adolescents with type 1 diabetes (age 17.3 ± 0.6 years and A1C 7.3 ± 0.3%) had two euglycemic glucose clamps during which 0.2 units/kg aspart and 0.4 units/kg detemir insulin were injected either as a separate or single mixed injection in random order.RESULTSMixing the two insulins diminished the peak and overall early aspart insulin action with significantly lower maximum glucose infusion rate (GIRmax separate 6.1 ± 0.7 mg/kg/min vs. mix 4.5 ± 0.5 mg/kg/min; P = 0.03) values and the area under curve for GIR during the first 3 h of the insulin action study (separate 757 ± 105 mg/kg vs. mix 491 ± 66 mg/kg; P = 0.04).CONCLUSIONSThese data demonstrate that mixing aspart with detemir insulin markedly lowers the early PD action of aspart and prolongs its time-action profile as compared with the separate injection of these analogs. These changes in insulin PD should be weighed against the added convenience of mixing when considering such unlicensed use of these insulins in youth with type 1 diabetes.

U‐100, pH‐Neutral formulation of VIAject®: faster onset of action than insulin lispro in patients with type 1 diabetes

VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid-Acting Insulin Using Needle-Free Jet Injection Technology

OBJECTIVEInsulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen.RESEARCH DESIGN AND METHODSEuglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively.RESULTSThe time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices.CONCLUSIONSAdministration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.

Intradermal Microneedle Delivery of Insulin Lispro Achieves Faster Insulin Absorption and Insulin Action than Subcutaneous Injection

This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions. Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5). Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites. Microneedle ID insulin lispro delivery enables more rapid onset and offset of metabolic effect than SC therapy and is safe and well tolerated; further study for insulin therapy is warranted.

Dose-Dependent Delay of the Hypoglycemic Effect of Short-Acting Insulin Analogs in Obese Subjects With Type 2 Diabetes

OBJECTIVEInjected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes.RESEARCH DESIGN AND METHODSEuglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m2) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the 133Xe-washout technique.RESULTSATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (Tmax) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (Cmax)/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIRmax: 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, Tmax (88.6 and 130.0 min, respectively) and time to GIRmax (175 and 245 min) were further delayed and dose related (r2 = 0.51, P = 0.0004 and r2 = 0.76, P < 0.0001, respectively).CONCLUSIONSAbsorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes.

Similarity of pharmacodynamic effects of a single injection of insulin glargine, insulin detemir and NPH insulin on glucose metabolism assessed by 24‐h euglycaemic clamp studies in healthy humans

Two long-acting insulin analogues, insulin glargine and insulin detemir, have been developed as alternatives to neutral protamine Hagedorn (NPH) insulin, which has been the preferred basal insulin preparation for decades. The aim was to directly compare the pharmacodynamic properties of the long-acting insulin analogues and NPH insulin after a single subcutaneous injection. The study was conducted as a double-blind, controlled, three-arm, crossover study including 10 healthy lean male volunteers. On three different occasions, each subject was challenged with 0.4 U kg(-1) of either insulin glargine, insulin detemir or NPH insulin. Plasma glucose was maintained at 0.3 mmol l(-1) below fasting level by glucose clamping for 24 h. C-peptide, insulin, free fatty acids (FFAs) and counter regulatory hormones were measured throughout the clamp period, whereas endogenous glucose release (EGR) was assessed by isotope dilution technique (3-(3)H-glucose). The mean glucose infusion rate (GIR)-time profiles revealed no significant differences between the three preparations in the primary endpoints: Maximal GIR of approximately 3.4 mg kg(-1) min(-1) (P = 0.68), time to maximal GIR of approximately 10 h (TR(max)) (P = 0.35) and area under the GIR curve (GIR(AUC)) (P = 0.81). Compared with the other insulin preparations, EGR (see above)was lower for insulin detemir at the beginning of the clamp period (330-360 min) (P = 0.007) while GIR was lower (P = 0.005) and FFA concentrations were higher (P = 0.005) during the last 4 h of the clamp. In this experimental design, only minor pharmacodynamic differences were demonstrated between insulin detemir, insulin glargine and NPH insulin.

Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

The objective of the study was to evaluate pharmacodynamic (PD) intrasubject variability of a single, s.c. dose of insulin lispro protamine suspension (ILPS) compared with insulin glargine in subjects with type 1 diabetes mellitus and additionally, to compare the intrasubject variability of pharmacokinetic parameters of both insulins. This was a single-center, investigator-blinded and subject-blinded, two-arm, parallel, randomized, four-period study. During the replicate visits, subjects received a single s.c. 0.6 U/kg dose of either ILPS or glargine, and underwent 24-h euglycemic glucose clamps. The intrasubject variabilities of the primary PD parameters, total amount of glucose infused (G(tot)) and maximum glucose infusion rate (GIR; R(max)), were statistically significantly lower for ILPS when compared with glargine (P<0.0001). Least-square (LS) mean estimates for G(tot) and R(max) were 2512.7 mg/kg and 3.740 mg/min per kg respectively for ILPS, and 1291.9 mg/kg and 1.793 mg/min per kg respectively for glargine. The LS mean estimates for G(tot) and R(max) were statistically greater (P=0.0010 and P<0.0001 respectively) for ILPS compared with glargine, suggesting that ILPS had greater 24-h glucose-lowering activity. Glargine demonstrated a flatter GIR-time curve, and ILPS demonstrated a significantly shorter time of maximum GIR (tR(max)) and earlier time to half-maximal GIR before tR(max) and time to half-maximal GIR after tR(max). ILPS administration resulted in significantly greater exposure compared with glargine (area under the baseline-corrected serum concentration versus time curve from time 0 to 24 h (AUC(0-24)): 77 150 vs 53 111 pmol min/l; maximum serum insulin concentration (C(max)): 119 vs 68 pmol/l; ILPS versus glargine respectively), but the intrasubject variabilities for AUC and C(max) were comparable. Although glargine demonstrated a flatter GIR-time profile, the lower PD intrasubject variability of ILPS may provide a more predictable response.

Dose-Response Effects of Insulin Glargine in Type 2 Diabetes

OBJECTIVETo determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSTwenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.RESULTSGlargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.CONCLUSIONA single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Pharmacokinetic/Pharmacodynamic Modeling of Glucose Clamp Effects of Inhaled and Subcutaneous Insulin in Healthy Volunteers and Diabetic Patients

The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (subcutaneous insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIR(max)) and 88.0 mIU/L for SC(50) for diabetic patients and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous insulin.

The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes

Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed. Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations.

AIR Insulin Capsules of Different Dose Strengths May Be Combined to Yield Equivalent Pharmacokinetics and Glucodynamics

In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects. Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose. Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range. AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.

Biphasic Insulin Aspart 30/70: Pharmacokinetics and Pharmacodynamics Compared With Once-Daily Biphasic Human Insulin and Basal-Bolus Therapy

OBJECTIVEPharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients.RESEARCH DESIGNS AND METHODSStudy 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h.RESULTSStudy 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg.CONCLUSIONSBIAsp had pharmacological advantages over BHI. BIAsp t.i.d. had a similar PD profile to basal-bolus therapy.

Accelerated Pharmacokinetics and Glucodynamics of Prandial Insulins Injected With Recombinant Human Hyaluronidase

This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20). Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight >70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G). For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P < 0.0001), increased early exposure (AUC(0-2h)) by 85% (P < 0.0001) and 211% (P < 0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P < 0.0001) and 48% (P < 0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P < 0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated. Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.