Lisbeth V. Jacobsen

Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Patients with Type 2 diabetes are likely to have or to develop renal impairment, which affects the pharmacokinetics of some antidiabetic treatments. * Whether dosing of the once-daily human glucagon-like peptide-1 analogue liraglutide should be modified in patients with renal impairment has not previously been studied. WHAT THIS STUDY ADDS * Renal dysfunction was not found to increase the exposure of liraglutide. * Hence, no dose adjustment is expected to be required in patients with Type 2 diabetes and renal impairment treated with liraglutide. AIMS To investigate whether dose adjustment of the once-daily human glucagon-like peptide-1 analogue liraglutide is required in patients with varying stages of renal impairment. METHODS A cohort of 30 subjects, of whom 24 had varying degrees of renal impairment and six had normal renal function, were given a single dose of liraglutide, 0.75 mg subcutaneously, and completed serial blood sampling for plasma liraglutide measurements for pharmacokinetic estimation. RESULTS No clear trend for change in pharmacokinetics was evident across groups with increasing renal dysfunction. While the between-group comparisons of the area under the liraglutide concentration-curve (AUC) did not demonstrate equivalence [estimated ratio AUC(severe)/AUC(healthy) 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)(CAPD)/AUC(healthy) 0.74, 90% CI 0.56, 0.97], the regression analysis of log(AUC) for subjects with normal renal function and mild-to-severe renal impairment showed no significant effect of decreasing creatinine clearance on the pharmacokinetics of liraglutide. The expected AUC ratio between the two subjects with the lowest and highest creatinine clearance in the study was estimated to be 0.88 (95% CI 0.58, 1.34) (NS). Degree of renal impairment did not appear to be associated with an increased risk of adverse events. CONCLUSIONS This study indicated no safety concerns regarding use of liraglutide in patients with renal impairment. Renal dysfunction was not found to increase exposure of liraglutide, and patients with Type 2 diabetes and renal impairment should use standard treatment regimens of liraglutide. There is, however, currently limited experience with liraglutide in patients beyond mild-stage renal disease.

Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: A double-blind crossover study in adults with type 2 diabetes mellitus

OBJECTIVE The purpose of this study was to compare the pharmacokinetics and pharmacodynamics of the premixed insulin analogue biphasic insulin aspart (BIAsp 30) with the equivalent premixed biphasic human insulin (BHI 30), administered twice daily, in patients with type 2 diabetes mellitus. METHODS In this randomized, double-blind, crossover trial, 13 patients (mean age, 64 years; baseline mean glycosylated hemoglobin, 7.7%; mean body mass index, 28.1 kg/m2) received 2 weeks of treatment with BIAsp 30 and 2 weeks of BHI 30 administered immediately before dinner and breakfast. At the end of each 2-week treatment period, 24-hour serum insulin and glucose profiles were determined using specific 2-sided enzyme-linked immunosorbent assays. All pharmacodynamic and pharmacokinetic end points were analyzed using analysis of variance. RESULTS Total daily insulin exposure was similar between treatment periods. Mean area under the total insulin concentration-time profile during the 2 hours following administration of BIAsp 30 was 17% greater than that of BHI 30 after dinner and 44% greater after breakfast; both differences were statistically significant. The maximum serum insulin aspart concentrations following BIAsp 30 were significantly higher after dinner (18%) and breakfast (35%). Peak serum insulin concentration was reached 1 hour earlier after breakfast and 45 minutes earlier after dinner in the BIAsp 30 group; differences were significant only after breakfast. The mean daily prandial glucose excursion was significantly lower for BIAsp 30 (16.2 mmol x h x L(-1)) than BHI 30 (17.9 mmol x h x L(-1)). Postprandial 4-hour glucose excursions were significantly lower with BIAsp 30 than with BHI 30 after dinner and breakfast, but were significantly greater after lunch. Mean 24-hour and nocturnal serum glucose concentrations were similar, and both insulins were associated with < or = 7 minor and no major hypoglycemic events. CONCLUSIONS Premeal injection of BIAsp 30 in a twice-daily regimen significantly reduced overall postprandial glucose excursions. This effect may be of importance when improvement in postprandial glucose control is desired.

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Aspart

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (tmax) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bio-availability of insulin aspart are similar to those of human insulin.The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent.Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia-induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen.This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro.

Population Pharmacokinetics of Liraglutide, a Once‐Daily Human Glucagon‐Like Peptide‐1 Analog, in Healthy Volunteers and Subjects With Type 2 Diabetes, and Comparison to Twice‐Daily Exenatide

The once‐daily human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide, was recently shown to provide improved glycemic control in subjects with type 2 diabetes (T2D) compared with exenatide. The aim of this work is to estimate the population pharmacokinetics of liraglutide and make a comparison to the pharmacokinetic profile of exenatide. Pharmacokinetic data from 5 published studies of subcutaneous and intravenous administration of liraglutide to healthy volunteers (HV) and subjects with T2D were used to develop a population pharmacokinetic model in NONMEM. Exenatide data came from a published study in T2D. Liraglutide pharmacokinetics were adequately described using a 1‐compartment model with sequential zero‐ and first‐order absorption. The pharmacokinetic profile of once‐daily liraglutide showed considerably smaller peak‐to‐trough fluctuations compared with twice‐daily exenatide. A small difference in the estimates of absorption parameters was found between HV and subjects with T2D but was not clinically relevant. It was concluded that pharmacokinetic profiles estimated by modeling showed that liraglutide has pharmacokinetic properties consistent with once‐daily dosing in humans and provides better pharmacokinetic coverage in comparison with twice‐daily exenatide. Furthermore, no clinically relevant differences were found in liraglutide pharmacokinetics between HV and subjects with T2D.

Liraglutide's safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. SUBJECTS AND METHODS Youth treated with diet/exercise alone or with metformin and having a hemoglobin A1c (HbA1c) level of 6.5-11% were randomized to liraglutide (n=14) or placebo (n=7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. RESULTS Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P=0.0007), whereas mean body weight remained stable (-0.50 vs. -0.54 kg, P=0.9703). CONCLUSIONS Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults.

Dosing Rationale for Liraglutide in Type 2 Diabetes Mellitus: A Pharmacometric Assessment

The glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose‐finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure‐response relationships for effects on fasting plasma glucose, hemoglobin A1c, and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure‐response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

Similarity of insulin detemir pharmacokinetics, safety, and tolerability profiles in healthy caucasian and Japanese american subjects.

The objective of this study was to compare the pharmacokinetics of insulin detemir in three ascending doses in healthy Japanese and Caucasian subjects. This was an open‐label, single‐center, parallel‐group design evaluating 30 subjects (15 Japanese and 15 Caucasians). Subjects received a total of three subcutaneous injections (one injection per visit) of insulin detemir (0.19, 0.38, 0.75 U/kg [1 U = 24 nmol]) in ascending order. Following drug administration, subjects received intravenous glucose in 0.5‐mg/kg/min increments every 30 minutes, followed by a constant rate of 2.0 mg/kg/min for up to 12 hours. For pharmacokinetic evaluations, serial blood sampling was performed over a period of 30 hours after dosing. Of the subjects, 36 were enrolled, and 30 completed the study. There was a linear dose‐response relationship between the three ascending insulin detemir doses and serum insulin detemir AUC values for both the Japanese and Caucasian subjects. The two dose‐response regression lines had equivalent slopes but slightly different intercepts (although not statistically significant). This difference may be due to variation in AUC, body weight differences, or chance. Six subjects discontinued the study, 2 as a result of adverse events (blood draw–related ecchymosis and hypoglycemia). The most frequent treatment‐emergent adverse events (TEAE) were headache, dizziness, and reactions related to blood draws/infusion sites. All TEAEs were mild to moderate in severity. The results show that an increase in insulin detemir dose will result in a similar increase in insulin detemir concentration in the two ethnic groups. Therefore, therapeutic dosing of insulin detemir is expected to be similar in both ethnic groups, with no special dose adjustment or algorithm based on race. Insulin detemir at 0.19, 0.38, and 0.75 U/kg was generally well tolerated in both Japanese and Caucasian subjects.

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Insulin degludec/liraglutide (IDegLira) is a novel fixed‐ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon‐like peptide‐1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single‐dose, randomized, 4‐period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure–response for change in glycated hemoglobin were analyzed based on data from a randomized treat‐to‐target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose‐lowering effects throughout the dose/exposure range.

Treatment With Liraglutide—a Once‐Daily GLP‐1 Analog—Does Not Reduce the Bioavailability of Ethinyl Estradiol/Levonorgestrel Taken as an Oral Combination Contraceptive Drug

Liraglutide is a once‐daily human GLP‐1 analog for treatment of type 2 diabetes. Like other GLP‐1 analogs, liraglutide delays gastric emptying, which could potentially affect absorption of concomitantly administered oral drugs. This study investigated the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive (ethinyl estradiol/levonorgestrel). Postmenopausal healthy women (n = 21) were included. A single dose of this contraceptive was administered. Blood samples for ethinyl estradiol/levonorgestrel measurements were drawn until 74 hours post dosing of the contraceptive during liraglutide and placebo treatments. The 90% confidence interval (CI) of the ratio of the area under the curve (AUC) (1.06; 90% CI, 0.99–1.13) for ethinyl estradiol (during liraglutide and placebo) was within defined limits, demonstrating equivalence. The 90% CI for the ratio of AUC for levonorgestrel was not fully contained within the limits (1.18; 90% CI, 1.04–1.34) (levonorgestrel AUC was 18% greater with liraglutide vs placebo). However, equivalence was demonstrated for levonorgestrel AUC0‐t (1.15; 90% CI, 1.06–1.24). Equivalence was not demonstrated for maximum concentration (Cmax); values for ethinyl estradiol and levonorgestrel Cmax were 12% and 13% lower with liraglutide versus placebo, respectively. Both reached Cmax ∼1.5 hours later with liraglutide. No clinically relevant reduction in bioavailability of ethinyl estradiol/levonorgestrel occurred.

The Pharmacokinetics, Pharmacodynamics, and Tolerability of Liraglutide, a Once‐Daily Human GLP‐1 Analogue, After Multiple Subcutaneous Administration in Healthy Chinese Male Subjects

In this single‐center, randomized, double‐blind, within dose group, placebo‐controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC0–24h, Cmax, and Ctrough at steady state do not deviate in a relevant way from dose proportionality. tmax and t1/2 were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2‐ and 1.8‐mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified.