Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0 mg: A model-based approach.

AIMS: To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon-like peptide-1 analogue liraglutide. MATERIALS AND METHODS: The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n = 4952) were analysed using a non-linear mixed-effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline glycated haemoglobin (HbA1c), age, gender, diabetes status (no diabetes, prediabetes or type 2 diabetes), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain after treatment cessation at week 56 (data not included in model development). RESULTS: A pharmacokinetic/pharmacodynamic model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than that recommended, one-week dose-escalation algorithms led up to 2 weeks slower initial weight loss but similar long-term weight loss trajectories. CONCLUSIONS: The relationship between liraglutide systemic exposure and weight loss was successfully established in overweight or obese people. The model could predict the time course of weight regain after treatment cessation and suggests that GI tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory.

Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide.

Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the K(m) for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency.

Pharmacokinetics and pharmacodynamics of rFVIIa and new improved bypassing agents for the treatment of haemophilia.

Animal models have played a critical role in developing our understanding of haemophilia and its treatment. For example, studies in mice and dogs have provided insights into the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa). Such studies have shown that antithrombin has a significant impact on clearance of rFVIIa, which explains discrepancies between the antigen and activity half-lives of rFVIIa. Animal studies have also shown that the major clearance organs for rFVIIa are the liver and the kidneys, whereas distribution studies suggest that FVII and rFVIIa leave the circulation and enter the tissues, before returning to the circulation through the lymph. One agent that has benefited greatly from the use of animal models in its development is vatreptacog alfa, a new analogue of rFVIIa. Promising in vitro results, including increased generation of FXa, shortened clotting times and increased clot stability, were subsequently confirmed in animal models. In a severe tail-bleed model in FVIII knock-out mice, reduction in maximal blood loss was substantially greater with vatreptacog alfa than with rFVIIa, FVIII or plasma-derived activated prothrombin complex concentrate. In a mouse model of joint bleeding, rFVIIa and vatreptacog alfa significantly reduced bleeding compared with vehicle-treated haemophilic controls. More recently, a model of endothelial injury based on mouse cremaster muscle has been developed. Overall, animal models are a valuable tool in elucidating the haemostatic process and the effects of therapeutic agents, although direct extrapolation to the clinical setting should be done with caution.

Blockade of NKG2D ameliorates disease in mice with collagen-induced arthritis: a potential pathogenic role in chronic inflammatory arthritis.

OBJECTIVE: To assess the role of the activating receptor NKG2D in arthritis. METHODS: Levels of NKG2D and its ligands were determined by fluorescence-activated cell sorting, real-time polymerase chain reaction, and immunohistochemistry in rheumatoid arthritis (RA) synovial membrane tissue and in paw tissue from arthritic mice. Arthritis was induced in DBA/1 mice by immunization with type II collagen, and mice were treated intraperitoneally with a blocking anti-NKG2D antibody (CX5) on days 1, 5, and 8 after clinical onset and were monitored for 10 days. RESULTS: We demonstrated expression of NKG2D and its ligands on human RA synovial cells and extended this finding to the paws of arthritic mice. Expression of messenger RNA for the NKG2D ligand Rae-1 was up-regulated, and NKG2D was present predominantly on natural killer (NK) and CD4+ T cells, in arthritic paw cell isolates. NKG2D was down-modulated during the progression of collagen-induced arthritis (CIA). NKG2D expression in arthritic paws was demonstrated by immunohistochemistry. Blockade of NKG2D ameliorated established CIA, with significant reductions in clinical scores and paw swelling. Histologic analysis of arthritic joints from anti-NKG2D-treated mice demonstrated significant joint protection, compared with control mice. Moreover, anti-NKG2D treatment significantly reduced both interleukin-17 production from CD4+ T cells in arthritic paws and splenic NK cell cytotoxic effector functions in vivo and in vitro. CONCLUSION: Our findings indicate that blockade of NKG2D in a murine model and in human explants has beneficial therapeutic potential that merits further investigation in RA.

Dose/exposure-response modeling in dose titration trials: Overcoming the titration paradox.

Response-based dose individualization or dose titration is a powerful approach to achieve precision dosing. Yet, titration as an individualization strategy is underused in drug development and therefore not reflected in labeling, possibly partly because of the data analysis challenges associated with assessing dose/exposure-response under dose titration, where there is an inherent risk of selection bias because poor responders would get high doses, whereas good responders would get low doses. In a recent article, this issue of selection bias was termed the "titration paradox." In this study, we demonstrate by means of simulation that the titration paradox may be overcome if longitudinal data from dose titration trials is analyzed using a population approach that accounts for the fact that dose/exposure-response relationships differ between individuals. We show that with an appropriate sample size and missing data missing at random, stepwise dose/exposure-response modeling based on data obtained under dose titration is not by definition subject to model selection bias or bias in parameter estimates. We also illustrate the challenges of graphical exploration of data obtained under dose titration and discuss the use of model diagnostic tools with such data. Our study shows that if, at every timepoint in the course of a trial, there is a clear causal relationship between the response and the dose/exposure level, and a population approach is used, it will in many cases be possible to develop, estimate, and appropriately qualify a dose/exposure-response model also for data obtained under dose titration, thus overcoming the titration paradox.

Intravascular inhibition of factor VIIa and the analogue NN1731 by antithrombin.

NN1731 is a recombinant activated factor VII (rFVIIa) analogue with increased intrinsic activity. This also applies to its reactivity towards antithrombin (AT), the role of which was investigated in a pharmacokinetic (PK) study. NN1731 or rFVIIa was administered to normal and haemophilia A dogs and elimination was measured by FVIIa clot activity, FVIIa- and FVIIa-AT antigen. In vitro AT complex formation was studied in canine plasma spiked with NN1731 or rFVIIa. Based on FVIIa antigen concentrations, PK profiles in normal and haemophilia A dogs were similar for NN1731 and rFVIIa with antigen half lives, t(½) ≈1·8 h. In contrast, PK profiles based on activity measurements were distinctly different. NN1731 induced a strong, short lasting (t(½) ≈0·5 h) pro-coagulant response, whereas rFVIIa induced a lower, longer lasting (t(½) ≈1·1 h) response. Western Blot and FVIIa-AT antigen analysis demonstrated in vivo AT complex formation that accounted for these divergences. AT complex formation with FVIIa or NN1731 in vitro in canine plasma was considerably slower than the in vivo reaction. The results suggest that in vivo inhibition by AT contributes significantly to define drug duration in haemophilia treatment with rFVIIa and in particular with the NN1731 analogue.

Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan.

CONTEXT: Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration. OBJECTIVE: To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing. DESIGN: A pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD. SETTING AND PATIENTS: 39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD. INTERVENTION(S): The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded. MAIN OUTCOME MEASURE(S): Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose. RESULTS: Robust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD < 0.2) and peak (RSD < 0.1), respectively. CONCLUSIONS: Linear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).

Population Pharmacokinetics and Pharmacodynamics of Once-Daily Growth Hormone Norditropin® in Children and Adults.

BACKGROUND AND OBJECTIVE: Once-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin®; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency. METHODS: A model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin® as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model. RESULTS: The model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children. CONCLUSIONS: The pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age. CLINICAL TRIAL REGISTRATION: Pooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783. DATES OF REGISTRATION: NCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.

Identification and preclinical development of an anti-proteolytic uPA antibody for rheumatoid arthritis.

Blocking the proteolytic capacity of urokinase-type plasminogen activator (uPA) with a monoclonal antibody (mAb) reduces arthritis progression in the collagen-induced mouse arthritis model to an extent that is on par with the effect of blocking tumor necrosis factor-alpha by etanercept. Seeking to develop a novel therapy for rheumatoid arthritis, a humanized mAb, NNC0266-0043, was selected for its dual inhibition of both the zymogen activation and the proteolytic capacity of human uPA. The antibody revealed nonlinear elimination kinetics in cynomolgus monkeys consistent with binding to and turnover of endogenous uPA. At a dose level of 20.6 mg kg-1, the antibody had a plasma half-life of 210 h. Plasma uPA activity, a pharmacodynamic marker of anti-uPA therapy, was reduced to below the detection limit during treatment, indicating that an efficacious plasma concentration was reached. Pharmacokinetic modeling predicted that sufficient antibody levels can be sustained in arthritis patients dosed subcutaneously once weekly. The anti-uPA mAb was also well tolerated in cynomolgus monkeys at weekly doses up to 200 mg kg-1 over 4 weeks. The data from cynomolgus monkeys and from human material presented here indicates that anti-uPA mAb NNC0266-0043 is suitable for clinical testing as a novel therapeutic for rheumatic diseases. KEY MESSAGES: Background: Anti-uPA therapy is on par with etanercept in a mouse arthritis model. A new humanized antibody blocks activation and proteolytic activity of human uPA. The antibody represents a radically novel mode-of-action in anti-rheumatic therapy. The antibody has PK/PD properties in primates consistent with QW clinical dosing.

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials.

BACKGROUND: Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen. OBJECTIVE: In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD. METHODS: Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.01-0.32 mg/kg; adult with GHD, 0.02-0.12 mg/kg; children with GHD, 0.02-0.16 mg/kg) using non-linear mixed-effects modeling. Pharmacokinetics were described using a non-linear one-compartment model with dual first- and zero-order absorption through a transit compartment, with saturable elimination. IGF-I profiles were described using an indirect response pharmacokinetic/pharmacodynamic model, with sigmoidal-effect relationship. RESULTS: The non-linear pharmacokinetic and IGF-I data were well-described in order to confidently predict pharmacokinetic/pharmacodynamic profiles after multiple doses in adults and children with GHD. Body weight was found to be a significant covariate, predictive of the differences observed in the pharmacokinetics and pharmacodynamics between children and adults. Weekly dosing of somapacitan provided elevated IGF-I levels throughout the week, despite little or no accumulation of somapacitan, in both adults and children with GHD. CONCLUSION: This analysis of somapacitan pharmacokinetic/pharmacodynamic data supports once-weekly dosing in adults and children with GHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers NCT01514500, NCT01706783, NCT01973244.

Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia.

Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults.

The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.

The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects.

UNLABELLED: The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP, previously known as gastric inhibitory polypeptide), is rapidly degraded to the biologically inactive metabolite GIP (3-42) in the circulation, but little is known about the kinetics of the intact hormone and the metabolite and whether differences exist between patients with type 2 diabetes mellitus and healthy subjects. We examined eight type 2 diabetic patients (six men, two women); mean (range) age: 59 (48-69) years; BMI: 31.6 (26.0-37.7) kg/m2; HbA1C: 9.0 (8.2-13.2) %; fasting plasma glucose (FPG): 10.0 (8.3-13.2) mmol/l and 8 healthy subjects matched for age, gender and BMI. An intravenous bolus injection of GIP (7.5 nmol) was given and venous blood samples were drawn the following 45 minutes. Peak concentrations of total GIP (intact+metabolite, mean+/-SEM) and intact GIP (in brackets) were 920+/-91 (442+/-52) pmol/l in the type 2 diabetic patients and 775+/-68 (424+/-30) pmol/l in the healthy subjects (NS). GIP was eliminated rapidly with the clearance rate for intact GIP being 2.3+/-0.2 l/min in the type 2 diabetic patients and 2.4+/-0.2 l/min in the healthy subjects (NS). The volumes of distributions were similar in the two groups and ranged from 8 to 21 l per subject. The primary metabolite, GIP 3-42, generated through the action of dipeptidyl peptidase IV (DPP-IV), was eliminated with a mean half-life of 17.5 and 20.5 min in patients and healthy subjects (NS). CONCLUSION: Elimination of GIP is similar in obese type 2 diabetic patients and matched healthy subjects. Differences in elimination of GIP and its primary metabolite, therefore, do not seem to contribute to the defective insulinotropic effect of GIP in type 2 diabetes.

The kidneys play a central role in the clearance of rhGH in rats.

The kidneys are thought to play an important role in the clearance of recombinant human growth hormone (rhGH), but the relative importance is not clear. Obtaining knowledge of clearance pathway is an important prerequisite for the development of new long acting growth hormone analogues targeted at treatment of patients with growth hormone disorders. The purpose of this study was to investigate the relative importance of the kidneys in the clearance of rhGH. The study employed a newly validated nephrectomy rat model and a population based pharmacokinetic approach to assess renal clearance of rhGH in non-anesthetized rats, anesthetized rats and in nephrectomized anesthetized rats. Clearance in non-anesthetized rats was 290 ml/h/kg. This was reduced to 185 ml/h/kg by anesthesia and further reduced to 18 ml/h/kg by nephrectomy. As nephrectomy was able to reduce clearance with 90%, we conclude that renal clearance plays a pivotal role in the elimination of rhGH in rats.

Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a potent glucose-lowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 +/- 7 years (mean +/- SD), BMI 28.9 +/- 3.0 kg/m(2), HbA(1c) 6.5 +/- 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 microg/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7-8 h) and mealtime (1130-1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg x kg(-1) x min(-1) every 10 min) was evaluated by 1-min sampled measurements of insulin concentrations from 0930 to 1030 h and subsequent time series analysis of the insulin concentration profiles. All results are given as NN2211 versus placebo; statistical analyses were performed by analysis of variance. In the fasting state, plasma glucose was significantly reduced (6.9 +/- 1.0 vs. 8.1 +/- 1.0 mmol/l; P = 0.004), ISR was increased (179 +/- 70 vs. 163 +/- 66 pmol/min; P = 0.03), and plasma glucagon was unaltered (19 +/- 4 vs. 20 +/- 4 pg/ml; P = 0.17) by NN2211. Meal-related area under the curve (AUC)(1130-1530 h) for glucose was markedly reduced (30.6 +/- 2.4 vs. 39.9 +/- 7.3 mmol x l(-1) x h(-1); P < 0.001), ISR AUC(1130-1530 h) was unchanged (118 +/- 32 vs. 106 +/- 27 nmol; P = 0.13), but the increment (relative to premeal values) was increased (65 +/- 22 vs. 45 +/- 11 nmol; P = 0.04). Glucagon AUC(1130-1530 h) was suppressed (77 +/- 18 vs. 82 +/- 17 pmol x l(-1) x h(-1); P = 0.04). Gastric emptying was significantly delayed as assessed by AUC(1130-1530 h) of 3-ortho-methylglucose (400 +/- 84 vs. 440 +/- 70 mg x l(-1) x h(-1); P = 0.02). During pulse entrainment, there was a tendency to increased high frequency regularity of insulin release as measured by a greater spectral power and autocorrelation coefficient (0.05 < P < 0.10). The pharmacokinetic profile of NN2211, as assessed by blood samplings for up to 63 h postdosing, was as follows: T(1/2) = 10.0 +/- 3.5 h and T(max) = 12.4 +/- 1.7 h. Two patients experienced gastrointestinal side effects on the day of active treatment. In conclusion, the long-acting GLP-1 derivative NN2211 effectively reduces fasting as well as meal-related (approximately 12 h postadministration) glycemia by modifying insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects.

OBJECTIVE: The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211. RESEARCH DESIGN AND METHODS: In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 microg/kg) with eight subjects per dose level at a 3:1 active:placebo randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211). RESULTS: After subcutaneous administration, the half-life of NN2211 was found to be 11-15 h. Overall, although there were no statistically significant differences compared with placebo in the area under the curve (0-9 h for insulin or glucagon), there was a borderline- significant lowering of glucose levels (P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion (P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment (notably headache, dizziness, nausea, and vomiting). CONCLUSIONS: This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans.

Pharmacokinetics and pharmacodynamics of a new formulation of recombinant human growth hormone administered by ZomaJet 2 Vision, a new needle-free device, compared to subcutaneous administration using a conventional syringe.

The objective of the present study was to investigate the applicability of a new human growth hormone (Zomacton) formulation, administered both by a conventional syringe and by a new needle-free device (ZomaJet 2 Vision). The study was performed according to a randomized, controlled, three-period crossover design. On 3 separate days, all subjects received in a random order a single subcutaneous injection of 1.67 mg hGH as follows: Zomacton 4 mg/ml conventional syringe administration (Treatment A), Zomacton 10 mg/ml conventional syringe administration (Treatment B), or Zomacton 10 mg/ml ZomaJet 2 Vision administration (Treatment C). The pharmacokinetic parameters were assessed for the individual subjects in each group by noncompartmental methods. Bioequivalence was assessed based on log-transformed AUC and C(max) values. To investigate the effectiveness of two formulations and the different administration methods, the pharmacodynamic parameters (insulin-like growth factor-1 [IGF-1] and free fatty acids [FFA]) were also evaluated. No subjects were withdrawn due to adverse events. The local tolerance assessment (assessed by inspection)revealed no differences between ZomaJet2 Vision application and conventional injections by syringe. Administration of the new hGH formulation by syringe was found to be bioequivalent with the reference treatment, both based on AUC and C(max) values; the new formulation administered by use of ZomaJet 2 Vision was found to be bioequivalent based on AUC values only. When using the ZomaJet 2 Vision, the absorption of hGH was faster, resulting in higher C(max) values. The maximum hGH serum concentration of around 20 ng/ml was observed 3.5 to 4 hours after drug administration. The terminal half-life was found to be around 2.5 hours. Comparison of the pharmacodynamic profiles (both IGF-1 and FFA) demonstrated bioequieffectiveness. These results support the use of jet injectors as a viable alternative to the traditional injection pens.

Pharmacodynamics of NN2211, a novel long acting GLP-1 derivative.

OBJECTIVE: To evaluate the effects of NN2211, a GLP-1 derivative, on glucose and insulin homeostasis in healthy volunteers by use of a nonlinear mixed-effects modeling approach. DESIGN: NN2211 is a GLP-1 derivative intended for the treatment of type 2 diabetes. In the present study, eight dose levels of NN2211 were tested in healthy human volunteers. Since NN2211 is only intended to have an effect when glucose levels are above baseline (thus limiting the risk of hypoglycaemia), no effects would be expected in healthy volunteers. In order to demonstrate effect in a phase 1 study including only healthy subjects, a glucose dose was administered i.v. 9 h after NN2211 dosing; the insulin response would then be expected to be improved (higher) in the subjects dosed with NN2211. METHODS: In the present work, the pharmacodynamic glucose and insulin response was modeled by fitting glucose and insulin data simultaneously with a nonlinear model incorporating known carbohydrate regulation mechanisms. After an initial model-building phase, the first-order approximation to the likelihood available in NONMEM was used to model the data. Placebo-dosed subjects were included in the analysis. RESULTS: It was possible to satisfactorily fit both insulin and glucose data simultaneously. The analysis demonstrated a dose proportional effect of NN2211 on the parameters controlling beta cell insulin secretion.

The dosing solution influence on the pharmacokinetics of degarelix, a new GnRH antagonist, after s.c. administration to beagle dogs.

OBJECTIVE: Degarelix (FE200486) is a new GnRH-receptor antagonist intended for the treatment of prostate cancer. The objective of the present analysis was to evaluate the pharmacokinetics of degarelix after subcutaneous (s.c.) and intra-muscular (i.m.) administration to male beagle dogs, and to determine the influence of the different dosing conditions on the absorption profile of degarelix. METHODS: Degarelix was administered to 27 dogs and plasma concentrations were measured. The dosing conditions varied with respect to route (s.c. or i.m.), dose (0.25-1.5 mg/kg), solution strength (1.25-40 mg/ml) and volume administered (0.15-2.9 ml). Data were analysed by use of non-linear mixed effect modelling to characterize the pharmacokinetics, in particular the relationship between dosing conditions and rate, and extent of absorption. RESULTS: After s.c. and i.m. administration of degarelix, the plasma concentration versus time profile was best described by applying a two-compartment model, with two input functions: a fast first-order input function to describe the rapid initial increase in the plasma concentration levels, and a slow first-order input function to describe the prolonged absorption profile of degarelix. Intra-muscular as opposed to s.c. administration led to a more rapid absorption of degarelix, reaching a mean maximum concentration of 64 and 31 ng/ml roughly 2.0 and 3.7 h after administration, respectively. The slow absorption half-life was found to be 268 h ( approximately 11 days). The relative fraction absorbed was found to vary with the concentration of the dosing solution. The present analysis suggested that the absorbed fraction was reduced by approximately 50% when the concentration in dosing solution was increased from 1.25 to 40 mg/ml. The rate of the initial absorption component was also dependent on the concentration in the dosing solution, with slower absorption at higher concentrations. CONCLUSION: Through varying the dosing conditions and by applying a joint analysis of all data, the important factors determining the complex absorption of degarelix could be described.