Background Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA(1c)) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. Methods This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m(2) or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2 center dot 4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA(1c); secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on ClinicalTrials.gov (NCT04982575) and is complete. Findings Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA(1c) from baseline to week 32 (CagriSema: -2 center dot 2 percentage points [SE 0 center dot 15]; semaglutide: -1 center dot 8 percentage points [0 center dot 16]; cagrilintide: -0 center dot 9 percentage points [0 center dot 15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1 center dot 3 percentage points [95% CI -1 center dot 7 to -0 center dot 8]; p<0 center dot 0001), but not versus semaglutide (-0 center dot 4 percentage points [-0 center dot 8 to 0 center dot 0]; p=0 center dot 075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15 center dot 6% [SE 1 center dot 26]; semaglutide: -5 center dot 1% [1 center dot 26]; cagrilintide: -8 center dot 1% [1 center dot 23]) was greater with CagriSema versus both semaglutide (p<0 center dot 0001) and cagrilintide (p<0 center dot 0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3 center dot 3 mmol/L [SE 0 center dot 3]; semaglutide: -2 center dot 5 mmol/L [0 center dot 4]; cagrilintide: -1 center dot 7 mmol/L [0 center dot 3]) was greater with CagriSema versus cagrilintide (p=0 center dot 0010) but not versus semaglutide (p=0 center dot 10). Time in range (3 center dot 9-10 center dot 0 mmol/L) was 45 center dot 9%, 32 center dot 6%, and 56 center dot 9% at baseline and 88 center dot 9%, 76 center dot 2%, and 71 center dot 7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. Interpretation In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA(1c) with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Combining sema (semaglutide 2.4 mg) and amylin analog cagri (cagrilintide 2.4 mg) has weight loss benefits, but the impact on HbA1c is unknown. This study is the first to assess the efficacy and safety of CagriSema (co-administered) vs sema or cagri alone in participants (pts) with T2D. In this phase 2 (NCT04982575), multicenter, double-blind trial, adults with T2D (HbA1c 7.5-10.0%) and BMI ≥27 kg/m2 on metformin ± SGLT2i, were randomized to once-weekly s.c. CagriSema, sema, or cagri for 32 weeks (all escalated over 16 weeks to 2.4 mg). The primary endpoint was change from baseline in HbA1c; key secondary endpoints were body weight and safety. Of the 92 pts randomized (64% male; mean age 58 years and T2D duration 8.7 years), those receiving CagriSema had significantly greater reductions in HbA1c (vs cagri) and body weight (vs sema and cagri) at week 32 (Figure). The proportion of pts achieving HbA1c <7.0% and ≤6.5%, were 89% and 75% for CagriSema, 69% and 48% for sema, and 33% and 17% for cagri at week 32. GI AEs were most common (58% for CagriSema, 32% for sema, and 33% for cagri), were mainly mild/moderate, occurred during dose escalation, and lead to treatment discontinuation in 0%, 3%, and 0% of pts with CagriSema, sema, and cagri, respectively; no level 2 or 3 hypoglycemia was reported. CagriSema improved glycemic control and led to significant weight loss vs both sema or cagri, and was well tolerated with no new safety signals. Disclosure J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. S.Macura: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

Continuous glucose monitoring (CGM) offers insight into glycemic levels beyond the conventional measurement of HbA1c. This phase 2, multicenter, 32-week, double-blind trial (NCT04982575) compared the effects of CagriSema (co-administered semaglutide [sema] 2.4 mg and cagrilintide [cagri] 2.4 mg) vs sema (2.4 mg) or cagri (2.4 mg) alone, all as once-weekly subcutaneous injection, on CGM parameters (secondary endpoints). In total, 92 adult participants with T2D (HbA1c 7.5-10.0%), on metformin ± SGLT2i, and BMI ≥27 kg/m2 were randomized. Time in range (70-180 mg/dL) increased in all groups, reaching 88.9% with CagriSema at week 32 (Figure). Time in tight range (70-140 mg/dL; post-hoc analysis) increased from 16.0%, 8.8%, and 26.2% at baseline to 66.4%, 50.0%, and 36.7% at week 32 for CagriSema, sema, and cagri, respectively, with 0.8% or less in time below range for all groups. Mean glucose (measured by CGM) decreased from baseline to week 32 (CagriSema, -63.9; sema, -43.6; cagri, -23.4 mg/dL; estimated treatment difference [95% CI]: CagriSema vs sema, -20.2 [-39.8, -0.7; p=0.04], and CagriSema vs cagri, -40.5 [-59.4, -21.6; p<0.0001] mg/dL). Time in range with CagriSema reached nearly 90% at week 32, with little time below range in the first trial of CagriSema in people with T2D. Furthermore, CagriSema led to a greater reduction in mean glucose vs both sema or cagri alone. Disclosure C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. E.W.Lehmann: Employee; Novo Nordisk A/S. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

Background Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose-response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. Methods We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m(2) or at least 27 kg/m(2) with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0.3, 0.6,1.2, 2.4, or 4.5 mg), once-daily liraglutide 3.0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov , NCT03856047, and is closed to new participants. Findings Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0.3-4.5 mg (100-102 per dose group), 99 to liraglutide 3.0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0.3-4.5 mg, 6.0%-10.8% [6.4-11.5 kg]) versus placebo (3.0% [3.3 kg]; estimated treatment difference range 3-0%-7.8%; p<0.001). Weight reductions were also greater with cagrilintide 4.5 mg versus liraglutide 3.0 mg (10.8% [11.5 kg] vs 9.0% [9.6 kg]; estimated treatment difference 1.8%, p=0.03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0.3-4.5 mg had gastrointestinal adverse events compared with placebo (41%-63% vs 32%), primarily nausea (20%-47% vs 18%). Interpretation Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Fast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp.

Aim To investigate the mechanisms behind the lower postprandial glucose (PPG) concentrations achieved with fast‐acting insulin aspart (faster aspart) than with insulin aspart (IAsp). Materials and methods In a randomized, double‐blind, crossover trial, 41 people with type 1 diabetes received identical subcutaneous single faster aspart and IAsp doses (individualized for each participant), together with a standardized mixed meal (including 75 g carbohydrate labelled with [1‐ 13 C] glucose). PPG turnover was determined by the triple‐tracer meal method using continuous, variable [6‐ 3 H] glucose and [6,6‐ 2 H 2 ] glucose infusion. Results Insulin exposure within the first hour was 32% greater with faster aspart than with IAsp (treatment ratio faster aspart/IAsp 1.32 [95% confidence interval {CI} 1.18;1.48]; P < .001), leading to a 0.59‐mmol/L non‐significantly smaller PPG increment at 1 hour (ΔPG 1h ; treatment difference faster aspart–IAsp −0.59 mmol/L [95% CI –1.19; 0.01]; P = .055). The trend towards reduced ΔPG 1h with faster aspart was attributable to 12% greater suppression of endogenous glucose production (EGP; treatment ratio 1.12 [95% CI 1.01; 1.25]; P = .040) and 23% higher glucose disappearance (1.23 [95% CI 1.05; 1.45]; P = .012) with faster aspart than with IAsp during the first hour. Suppression of free fatty acid levels during the first hour was 36% greater for faster aspart than for IAsp (1.36 [95% CI 1.01;1.88]; P = .042). Conclusions The trend towards improved PPG control with faster aspart vs IAsp in this study was attributable to both greater early suppression of EGP and stimulation of glucose disappearance.

BACKGROUND:Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with additional excipients (L-arginine and niacinamide). In adults, faster aspart provides faster onset and greater early exposure and action vs IAsp. AIM:This randomized, double-blind, 2-period crossover trial investigated the pharmacological properties of faster aspart vs IAsp in 12 children (6-11 years), 13 adolescents (12-17 years), and 15 adults (18-64 years) with type 1 diabetes mellitus. METHODS:Subjects received 0.2 U/kg subcutaneous dosing (mean of 8.3, 12.8, and 15.6 U, respectively) immediately prior to a standardized meal (17.3 g carbohydrate/100 mL; amount adjusted by body weight). RESULTS:Consistently across age groups, onset of appearance occurred approximately twice-as-fast (5-7 minutes earlier) and early exposure (AUCIAsp,0-30min ; area under the IAsp curve from 0 to 30 minutes) was greater (by 78%-147%) for faster aspart vs IAsp, with no treatment differences in total exposure (AUCIAsp,0-t ) or maximum concentration (C max ). Two-hour postmeal plasma glucose excursion was reduced for faster aspart vs IAsp (although only reaching statistical significance in children). In accordance with the absolute dose administered for each age group, AUCIAsp,0-t for faster aspart was lower in children (estimated ratio children/adults [95% confidence interval]: 0.59 [0.50;0.69], P < .001) and adolescents (0.78 [0.67;0.90], P = .002) vs adults. No age group differences were seen in C max (0.91 [0.70;1.17], P = .445, and 0.99 [0.77;1.26], P = .903). The age effect on AUCIAsp,0-t and C max did not differ statistically significantly between treatments. Faster aspart and IAsp were well-tolerated. CONCLUSION:The current findings in children and adolescents suggest a potential for faster aspart to improve postprandial glycemia over current rapid-acting insulins also in younger age groups. http://ClinicalTrials.gov identifier: NCT02035371.

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared.

Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval.

Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) set in a new formulation with added excipients and faster initial absorption after subcutaneous (SC) injection. This pooled analysis of pharmacokinetic/pharmacodynamics (PK/PD) properties of faster aspart vs. IAsp included 218 adult subjects with type 1 diabetes from 6 phase-1, randomized, double-blind, crossover trials. Subjects received single SC doses (0.2 U/kg) of faster aspart and IAsp. In 3 trials, a 12-hour automated euglycaemic clamp was performed (target 100 mg/dL). Onset of appearance was twice as fast (~5 minutes earlier) (Table 1) and time to 50% of maximum serum IAsp concentration (t50%Cmax) was 9.5 minutes earlier with faster aspart than with IAsp, resulting in 2-fold higher insulin exposure during the first 30 minutes and higher insulin exposure up to 2 hours after injection with faster aspart vs. IAsp. The higher early exposure of faster aspart translated into a left shift of the glucose-lowering effect profile. Onset of action was 23% faster, time to 50% of maximum glucose infusion rate (t50%GIRmax) was 21% earlier and the glucose-lowering effect during the first 30 minutes was 74% greater with faster aspart vs. IAsp. Total exposure, maximum concentration, and total and maximum glucose-lowering effect were similar between treatments. In conclusion, in a pooled analysis, faster aspart demonstrated faster onset and higher early insulin exposure that led to greater early glucose-lowering effect vs. IAsp. Table 1Pharmacokinetic and pharmacodynamic results for faster aspart vs. IAsp PK endpoints(insulin exposure a Based on free serum IAsp. ) n=261/256 b n is number of profiles contributing to the analysis for faster aspart/IAsp. PD endpoints (glucose-lowering effect) n=163/160 b n is number of profiles contributing to the analysis for faster aspart/IAsp. Onset Treatment differenceFaster aspart–IAsp [95% CI] (min) Onset Treatment differenceFaster aspart–IAsp[95% CI] (min) Onset of appearancet50%Cmax –4.9 [–5.3;–4.4]–9.5 [–10.7;–8.3] Onset of actiont50%GIRmax –4.9 [–6.9;–3.0]–9.5 [–12.5;–6.4] Early exposure Treatment ratioFaster aspart/IAsp [95% CI] Early effect Treatment ratioFaster aspart/IAsp[95% CI] AUC0–15 min 3.83 [3.41;4.29] – – AUC0–30 min 2.01 [1.87;2.17] AUCGIR,0–30 min 1.74 [1.47;2.10] c treatment ratio and 95% CI estimated using Fieller's method. AUC0–1h 1.32 [1.26;1.39] AUCGIR,0–1h 1.34 [1.25;1.43] AUC0–2h 1.10 [1.06;1.14] AUCGIR,0–2h 1.13 [1.07;1.19] Total exposure Treatment ratioFaster aspart/IAsp[95% CI] Total effect Treatment ratioFaster aspart/IAsp[95% CI] AUC0–12h 1.01 [0.98;1.04] AUCGIR,0–12h 0.98 [0.94;1.03] Cmax 1.04 [1.00;1.08] GIRmax 1.01 [0.96;1.05] AUC, area under the curve; CI, confidence interval; Cmax, maximum observed concentration; GIRmax, maximum glucose infusion rate; onset of appearance, time from dosing until the first time serum IAsp concentration≥lower limit of quantification. a Based on free serum IAsp. b n is number of profiles contributing to the analysis for faster aspart/IAsp. c treatment ratio and 95% CI estimated using Fieller's method. Open table in a new tab AUC, area under the curve; CI, confidence interval; Cmax, maximum observed concentration; GIRmax, maximum glucose infusion rate; onset of appearance, time from dosing until the first time serum IAsp concentration≥lower limit of quantification.

Objective The aim of this study was to characterise the population pharmacokinetics of FE 999049, a novel recombinant human follicle-stimulating hormone (FSH), after multiple dosing in healthy women, taking into account endogenous FSH levels and the reproductive hormone dynamics.Methods Longitudinal measurements of FSH, luteinising hormone, progesterone, estradiol, and inhibin B levels were collected after repeated subcutaneous dosing with 225 IU of FE 999049 in 24 gonadotropin downregulated healthy women. The FSH data were described using nonlinear mixed-effects modelling.Results The measured FSH levels were modelled as a sum of endogenous FSH and FE 999049. The FE 999049 population pharmacokinetics were best described using a one-compartment model with first-order absorption and elimination, and a transit model for delayed absorption. The apparent clearance and volume of distribution increased with body weight in accordance with an allometrically scaled power exponent of 0.75 and 1, respectively. Endogenous FSH levels were lower in individuals with higher progesterone levels at baseline and were further suppressed over time with increasing inhibin B levels.Conclusions This characterisation of FE 999049 population pharmacokinetics after repeated dosing is in line with previous findings after single-dose administration. The results provide a basis for study design and data evaluation in the future development of recombinant FSH products, and show it can be of importance to account for endogenous FSH levels and its variation over time for accurate estimation of exogenously administered FSH pharmacokinetic parameters. Thus, correcting FSH concentrations by the observed endogenous FSH baseline value at all time points may be incorrect.

The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6®) developed for controlled ovarian stimulation prior to assisted reproductive technologies.

Population approaches are more robust estimators of insulin sensitivity (SI) and glucose effectiveness (SG) with the minimal model of glucose kinetics during an intravenous glucose tolerance test (IVGTT). We assessed the performance of 3 population methods, iterative two-stage (ITS), Bayesian hierarchical Markov chain Monte Carlo (MCMC), and NONMEM first-order conditional estimation (FOCE) with interaction (NM), and made a comparison with the standard two-stage method (STS) employing the weighted nonlinear regression analysis. To evaluate accuracy of individual and population estimates, 40 simulated insulin-modified frequently sampled IVGTTs (IM-FSIVGTT) were derived from real IM-FSIVGTTs (0.3 g glucose per kg body weight with 0.02 U/kg insulin at 20 minutes; 30 samples over 180 minutes) performed in 40 healthy Caucasian subjects (male/female, 22/18; age, 46 +/- 9 years; body mass index [BMI], 26.7 +/- 5.7 kg. m(-2); mean +/- SD). The population methods assumed a log-normal population distribution of parameters. All methods gave a similar but overestimated population SG by 9% to 13%. Population SI was underestimated to a different degree by the methods (STS 6%, ITS 10%, MCMC 13%, and NM 7%). The between-subject variability of SG was overestimated by STS and underestimated by the population methods (true 33%, STS 40%, ITS 19%, MCMC 24%, NM 24%; coefficient of variation). For SI, this quantity was well estimated by all methods (true 79%, STS 80%, ITS 82%, MCMC 83%, NM 82%). The results for individual estimates indicate that STS performs better than the population methods when estimating SI (STS 12%, ITS 16%, MCMC 16%, NM 16%; 1 outlying subject excluded; root mean squared error expressed as percent of mean) but worse for SG (STS 28%, ITS 21%, MCMC 20%, NM 19%). We conclude that the robust performance of population approaches, preventing parameter estimation failures associated with the nonlinear regression analysis, is not required with IM-FSIVGTT in subjects with normal glucose tolerance. The standard two-stage technique is the preferred method under such circumstances.

In this paper we apply a statistical model combining a random coefficient regression model and a latent class regression model. The EM-algorithm is used for maximum likelihood estimation of the unknown parameters in the model and it is pointed out how this leads to a straightforward handling of a number of different variance/covariance restrictions. Finally, the model is used to analyze how consumers' preferences for eight coffee samples relate to sensory characteristics of the coffees. Within this application the analysis corresponds to a model-based version of the so-called external preference mapping.