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Charlotte Kloft - One of the best experts on this subject based on the ideXlab platform.

  • A quantitative enterohepatic circulation model: development and evaluation with Tesofensine and meloxicam.
    Clinical Pharmacokinectics, 2012
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Christiane Tillmann, Charlotte Kloft
    Abstract:

    Background and Objective Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t1/2). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of Tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of Tesofensine and meloxicam to various extents.

  • Quantitative Pharmacology Approach in Alzheimer’s Disease: Efficacy Modeling of Early Clinical Data to Predict Clinical Outcome of Tesofensine
    The AAPS Journal, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Effective therapeutic options for Alzheimer’s disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of Tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of Tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for Tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For Tesofensine, the dose concentration–effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

  • Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of Tesofensine.
    Aaps Journal, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Effective therapeutic options for Alzheimer’s disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of Tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of Tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for Tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For Tesofensine, the dose concentration–effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

  • Semi-Mechanistic Population Pharmacokinetic Drug-Drug Interaction Modelling of a Long Half-Life Substrate and Itraconazole
    Clinical Pharmacokinetics, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Background: For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach. Objectives: To accomplish a semi-mechanistic DDI model for a long-elimination-half-life drug substrate, Tesofensine, and the cytochrome P450 (CYP) 3 A4 inhibitor itraconazole, and to compare the results of the semi-mechanistic model with the results obtained from the standard NCA approach. Additionally, the impact of different schedules of itraconazole on Tesofensine pharmacokinetics and the general performance of the standard NCA approach were evaluated. Methods: Overall, 28 subjects received a single oral dose of Tesofensine 2 mg; 14 of these subjects were coadministered an oral itraconazole 400 mg loading dose and a 200 mg maintenance dose for 6 days before and 5 days after administration of Tesofensine. The dataset contained 465 plasma concentrations of Tesofensine (full profiles) and 80 plasma concentrations of itraconazole (trough values). First, pharmacokinetic models of itraconazole and Tesofensine were developed in parallel. Subsequently, a combined model was developed, taking into account CYP3A4 inhibition. The analyses were performed using NONMEM® software. Results: The plasma concentration-time profiles of itraconazole and Tesofensine were best described by a one-compartment model for each drug, with first-order elimination rate constants that were both inhibited by itraconazole concentrations. Inhibition resulted in reduced clearances and prolonged elimination half-lives for Tesofensine and itraconazole: using NCA, the actual study revealed an ∼9% increase in exposure for the timeframe of the coadministration with itraconazole (the area under the plasma concentration-time curve (AUC) from 0 to 144 hours [AUC_144h]), and the impact on exposure estimated to infinity (AUC_∞) was ∼26%. These results are in contrast to the model-predicted results, where the inhibitory effect of itraconazole caused a 38% reduction in the clearance of Tesofensine, leading to a 63% increased exposure. Conclusions: This analysis presents a semi-mechanistic population pharmacokinetic approach that may be useful for the evaluation of DDI studies. The model can be an aid in evaluating DDI studies for compounds with a long elimination half-life, especially when the inhibitor cannot be administered over a sufficient period. Additionally, the population model-based approach may allow simplification of the design and the analysis and interpretation of safety and efficacy findings in DDI studies.

  • A Quantitative Enterohepatic Circulation Model
    Clinical Pharmacokinetics, 2009
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Christiane Tillmann, Charlotte Kloft
    Abstract:

    Background and Objective Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t_1/2). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of Tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of Tesofensine and meloxicam to various extents. Methods Two studies were investigated retrospectively for model development and model evaluation. Twentyone healthy subjects received a single 6-hour infusion of Tesofensine (0.3, 0.6, 0.9, 1.2 mg) in a double-blind, randomized, placebo-controlled, single rising-dose study. Twelve healthy subjects were treated in a randomized, crossover study with meloxicam 30 mg as a single dose given intravenously (bolus) either alone or concomitantly with cholestyramine. The EHC model was developed based on data from the Tesofensine study, where EHC is suspected. Model evaluation was performed with data from the meloxicam trial. Modelling and simulation analyses were performed using the software programs NONMEM, SAS and Berkeley Madonna. Results Plasma concentration-time profiles of Tesofensine were best described by a three-compartment model (absorption, central and gallbladder) with first-order elimination. The release of the bile compartment was controlled by a sine function model, switching the bile compartment periodically on and off using the actual clock time as the control element. A four-compartment model (absorption, central, peripheral and gallbladder) with first-order elimination and the sine function for gallbladder control described the meloxicam data best. Coadministration of cholestyramine resulted in a predicted 56% withdrawal of meloxicam from the EHC process causing a reduction in the t_1/2 from ∼19 hours to ∼12 hours. Conclusion A quantitative EHC model was successfully developed that was capable of describing the multiple peaks in plasma concentration-time profiles of Tesofensine and meloxicam very well. Additionally, the model successfully quantified the observed results for an interruption of the meloxicam EHC. The model offers an in silico method to support an EHC hypothesis using standard pharmacokinetic data and might help to guide dosing recommendations of compounds undergoing EHC.

Arne Astrup - One of the best experts on this subject based on the ideXlab platform.

  • The Effect of Tesofensine on appetite
    2012
    Co-Authors: Christoph Gasteyger, Arne Astrup, A Raben, Dieter H. Meier, Anders Sjödin
    Abstract:

    Tesofensine (TE), an inhibitor of monoamine presynaptic reuptake, has produced twice the weight loss seen with currently marketed drugs. However, its long term effect on appetite in humans has not been studied. A multicentre phase II trial was divided into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg TE, or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg TE. Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 − hunger) + (100 − prospective food consumption) were assessed. In Part 1 TE induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001). However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants’ reduced-weight state (−7.2 ± 6.7 kg, P < 0.0001). The reintroduction of TE in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss. Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of TE per se diminishes over time is, however, still unclear.

  • The Effect of Tesofensine on Appetite Sensations
    Obesity, 2011
    Co-Authors: Jo-anne Gilbert, Anne Raben, Arne Astrup, Christoph Gasteyger, Dieter H. Meier, Anders Sjödin
    Abstract:

    Tesofensine (TE), an inhibitor of monoamine presynaptic reuptake, has produced twice the weight loss seen with currently marketed drugs. However, its long term effect on appetite in humans has not been studied. A multicentre phase II trial was divided into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg TE, or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg TE. Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 − hunger) + (100 − prospective food consumption) were assessed. In Part 1 TE induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001). However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants' reduced-weight state (−7.2 ± 6.7 kg, P < 0.0001). The reintroduction of TE in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss. Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of TE per se diminishes over time is, however, still unclear.

  • The effect of the triple monoamine reuptake inhibitor Tesofensine on energy metabolism and appetite in overweight and moderately obese men
    International Journal of Obesity, 2010
    Co-Authors: Anders Sjödin, Anne-louise Hother Nielsen, Christoph Gasteyger, A Raben, Dieter H. Meier, J.d. Mikkelsen, J. K. S. Jensen, Arne Astrup
    Abstract:

    Tesofensine (TE) is a new drug producing twice the weight loss in obese individuals as seen with currently marketed drugs. It inhibits the presynaptic reuptake of the neurotransmitters noradrenaline, dopamine and serotonin, and is thought to enhance the neurotransmission of all three monoamines. The mechanisms by which it produces weight loss in humans are unresolved. The aim of this study is to investigate the mechanism(s) behind weight reduction by measuring energy expenditure and appetite sensations in overweight and obese individuals. Thirty-two healthy, overweight or moderately obese men were treated with 2.0 mg TE daily for 7 days followed by an additional 7 days with 1.0 mg TE daily or corresponding placebo (PL) in a randomized, controlled trial. They were instructed to maintain habitual food intake and physical activity throughout. Twenty-four-hour energy expenditure (24-h EE), fat oxidation and spontaneous physical activity were measured in a respiration chamber before and after treatment. Body composition was assessed by dual-energy X-ray absorption and appetite was evaluated by visual analogue scales in conjunction with a standardized dinner. Despite efforts to keep body weight and composition constant, TE induced a 1.8 kg weight loss above PL after 2 weeks’ treatment (P

  • the effect of the triple monoamine reuptake inhibitor Tesofensine on energy metabolism and appetite in overweight and moderately obese men
    International Journal of Obesity, 2010
    Co-Authors: Anders Sjödin, Anne-louise Hother Nielsen, Christoph Gasteyger, A Raben, Dieter H. Meier, J.d. Mikkelsen, J. K. S. Jensen, Arne Astrup
    Abstract:

    Tesofensine (TE) is a new drug producing twice the weight loss in obese individuals as seen with currently marketed drugs. It inhibits the presynaptic reuptake of the neurotransmitters noradrenaline, dopamine and serotonin, and is thought to enhance the neurotransmission of all three monoamines. The mechanisms by which it produces weight loss in humans are unresolved. The aim of this study is to investigate the mechanism(s) behind weight reduction by measuring energy expenditure and appetite sensations in overweight and obese individuals. Thirty-two healthy, overweight or moderately obese men were treated with 2.0 mg TE daily for 7 days followed by an additional 7 days with 1.0 mg TE daily or corresponding placebo (PL) in a randomized, controlled trial. They were instructed to maintain habitual food intake and physical activity throughout. Twenty-four-hour energy expenditure (24-h EE), fat oxidation and spontaneous physical activity were measured in a respiration chamber before and after treatment. Body composition was assessed by dual-energy X-ray absorption and appetite was evaluated by visual analogue scales in conjunction with a standardized dinner. Despite efforts to keep body weight and composition constant, TE induced a 1.8 kg weight loss above PL after 2 weeks’ treatment (P<0.0001). TE also induced higher ratings of satiety and fullness and concomitantly lower prospective food intake than placebo. No significant effect of TE on total 24-h EE could be demonstrated compared with PL, but higher energy expenditure was observed during the night period (4.6%; P<0.05) when adjusted for changes in body composition. Furthermore, TE increased 24-h fat oxidation as compared with PL (18 g; P<0.001). TE has a pronounced effect on appetite sensations and a slight effect on energy expenditure at night—both effects can contribute to the strong weight-reducing effect of TE.

  • The effect of Tesofensine on body weight and body composition in obese subjects--secondary publication
    Ugeskrift for Læger, 2009
    Co-Authors: Anne-louise Hother Nielsen, Thomas Larsen, Sten Madsbad, Leif Breum, Thomas Jensen, Jens Peter Kroustrup, Arne Astrup
    Abstract:

    Results from a phase II trial with Tesofensine for treatment of obesity are presented. In total 203 obese persons were randomised to treatment with Tesofensine 0.25, 0.5, or 1.0 mg, or placebo daily for 24 weeks. Treatment with Tesofensine resulted in a mean weight reduction of 4.5, 9.2 and 10.6% higher than that of placebo for 0.25, 0.5 and 1.0 mg, respectively. Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.

Henrik H. Hansen - One of the best experts on this subject based on the ideXlab platform.

  • Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat.
    Pharmacology Biochemistry and Behavior, 2013
    Co-Authors: Henrik H. Hansen, Majbrit M. Jensen, Agnete Overgaard, Pia Weikop, Jens D Mikkelsen
    Abstract:

    Abstract Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of Tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, Tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that Tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.

  • Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of Tesofensine in rats.
    Obesity, 2013
    Co-Authors: Bo Hjorth Bentzen, Morten Grunnet, Lars Hyveled-nielsen, Claus Sundgreen, Jørgen Buus Lassen, Henrik H. Hansen
    Abstract:

    Objective: Tesofensine is a novel triple monoamine reuptake inhibitor which is in development for the treatment of obesity. Preclinical and clinical data suggest that appetite suppression is an important mechanism by which Tesofensine exerts its robust weight reducing effect. Notably, the strong hypophagic response to Tesofensine treatment is demonstrated to be linked to central stimulation of noradrenergic and dopaminergic neurotransmission. The sympathomimetic mode of action of Tesofensine may also associate with the elevated heart rate and blood pressure observed in clinical settings, and we therefore sought experimentally to address this issue. Design and Methods: The anorexigenic and cardiovascular effects of Tesofensine were studied simultaneously in telemetrized conscious rats in a combined real-time food intake and cardiovascular telemetry monitoring system. Results: Acute administration of Tesofensine caused a dose-dependent hypophagic effect as well as increased heart rate and blood pressure. Interestingly, combined treatment with metoprolol (b1 adrenoceptor blocker, 10-20 mg/kg, p.o.) fully prevented the cardiovascular sympathetic effects of Tesofensine while leaving the robust inhibitory efficacy on food intake unaffected. Similarly, the angiotensin AT1 receptor antagonist telmisartan (1.0-3.0 mg/kg, p.o.) did not interfere with the anti-obesity effects of Tesofensine, however, telmisartan only partially reversed the increase in systolic blood pressure and had no effect on the elevated heart rate induced by Tesofensine. Conclusion: These data suggests that Tesofensine causes elevations in heart rate and blood pressure by increasing sympathetic activity, and that different adrenoceptor subtypes may be responsible for the anti-obesity and cardiovascular effects of Tesofensine.

  • Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α_1 Adrenoceptor and Dopamine D_1 Receptor Pathways in the Diet-Induced Obese Rat
    Neuropsychopharmacology, 2010
    Co-Authors: Anne Marie D Axel, Jens D Mikkelsen, Henrik H. Hansen
    Abstract:

    Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of Tesofensine. DIO rats treated with Tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period, Tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with Tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5–3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED_50 of 1.3 mg/kg. The hypophagic response of Tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, α _1 adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D_1 receptor antagonist). In contrast, Tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, α _2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D_2 receptor antagonist), NGB2904 (0.1 mg/kg, D_3 receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT_2A/C receptor antagonist). Hence, the mechanism underlying the suppression of feeding by Tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate α _1 adrenoceptor and DA D_1 receptor function.

  • The novel triple monoamine reuptake inhibitor Tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant.
    European journal of pharmacology, 2010
    Co-Authors: Henrik H. Hansen, Gitte Hansen, Mads Tang-christensen, Philip J Larsen, Anne Marie D Axel, Anne Raben, Jens D Mikkelsen
    Abstract:

    Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of Tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators. Compared to baseline, long-term treatment with Tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose of rimonabant (10mg/kg, p.o.) only produced a transient weight reduction. While all compounds exhibited a significant inhibitory effect on food intake which gradually wore off, the hypophagic effect of Tesofensine was longer lasting than sibutramine and rimonabant. In contrast to Tesofensine, the body weight of pair-fed rats returned to baseline at the end of the study, which may indicate that Tesofensine stimulated energy expenditure. The differential efficacy on weight reduction was also reflected in lowered body fat depots, as Tesofensine and sibutramine most efficiently reduced abdominal and subcutaneous fat mass which was paralleled by reduced plasma lipid levels. In an oral glucose tolerance test, only Tesofensine significantly suppressed the plasma insulin response below the level that could be obtained by paired feeding, indicating that Tesofensine further improved glycemic control. In conclusion, the robust weight loss with long-term Tesofensine treatment is likely due to a combined synergistic effect of appetite suppression and increased energy expenditure.

  • Tesofensine, A NOVEL TRIPLE MONOAMINE REUPTAKE INHIBITOR, INDUCES APPETITE SUPPRESSION BY INDIRECT STIMULATION OF α1 ADRENOCEPTOR AND D1 DOPAMINERGIC RECEPTOR PATHWAYS IN THE DIET-INDUCED OBESE RAT
    Neuropsychopharmacology, 2010
    Co-Authors: Anne Marie D Axel, Jens Damsgaard Mikkelsen, Henrik H. Hansen
    Abstract:

    Tesofensine is a novel monoamine reuptake inhibitor (MRI) which inhibits both norepinephrine, 5-HT and dopamine reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of Tesofensine. DIO rats treated with Tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12h nocturnal test period, Tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with Tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED50 of 1.3 mg/kg. The hypophagic response of Tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, α1 adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, dopamine D1 receptor antagonist). In contrast, Tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, α2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D2 receptor antagonist), NGB2904 (0.1 mg/kg, D3 receptor antagonist), ritanserin (0.03 mg/kg, 5-HT2A/C receptor antagonist). Hence, the mechanism underlying the suppression of feeding by Tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate α1 adrenoceptor and dopamine D1 receptor function.

Thorsten Lehr - One of the best experts on this subject based on the ideXlab platform.

  • A quantitative enterohepatic circulation model: development and evaluation with Tesofensine and meloxicam.
    Clinical Pharmacokinectics, 2012
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Christiane Tillmann, Charlotte Kloft
    Abstract:

    Background and Objective Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t1/2). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of Tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of Tesofensine and meloxicam to various extents.

  • Quantitative Pharmacology Approach in Alzheimer’s Disease: Efficacy Modeling of Early Clinical Data to Predict Clinical Outcome of Tesofensine
    The AAPS Journal, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Effective therapeutic options for Alzheimer’s disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of Tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of Tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for Tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For Tesofensine, the dose concentration–effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

  • Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of Tesofensine.
    Aaps Journal, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Effective therapeutic options for Alzheimer’s disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of Tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of Tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for Tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For Tesofensine, the dose concentration–effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

  • Semi-Mechanistic Population Pharmacokinetic Drug-Drug Interaction Modelling of a Long Half-Life Substrate and Itraconazole
    Clinical Pharmacokinetics, 2010
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Charlotte Kloft
    Abstract:

    Background: For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach. Objectives: To accomplish a semi-mechanistic DDI model for a long-elimination-half-life drug substrate, Tesofensine, and the cytochrome P450 (CYP) 3 A4 inhibitor itraconazole, and to compare the results of the semi-mechanistic model with the results obtained from the standard NCA approach. Additionally, the impact of different schedules of itraconazole on Tesofensine pharmacokinetics and the general performance of the standard NCA approach were evaluated. Methods: Overall, 28 subjects received a single oral dose of Tesofensine 2 mg; 14 of these subjects were coadministered an oral itraconazole 400 mg loading dose and a 200 mg maintenance dose for 6 days before and 5 days after administration of Tesofensine. The dataset contained 465 plasma concentrations of Tesofensine (full profiles) and 80 plasma concentrations of itraconazole (trough values). First, pharmacokinetic models of itraconazole and Tesofensine were developed in parallel. Subsequently, a combined model was developed, taking into account CYP3A4 inhibition. The analyses were performed using NONMEM® software. Results: The plasma concentration-time profiles of itraconazole and Tesofensine were best described by a one-compartment model for each drug, with first-order elimination rate constants that were both inhibited by itraconazole concentrations. Inhibition resulted in reduced clearances and prolonged elimination half-lives for Tesofensine and itraconazole: using NCA, the actual study revealed an ∼9% increase in exposure for the timeframe of the coadministration with itraconazole (the area under the plasma concentration-time curve (AUC) from 0 to 144 hours [AUC_144h]), and the impact on exposure estimated to infinity (AUC_∞) was ∼26%. These results are in contrast to the model-predicted results, where the inhibitory effect of itraconazole caused a 38% reduction in the clearance of Tesofensine, leading to a 63% increased exposure. Conclusions: This analysis presents a semi-mechanistic population pharmacokinetic approach that may be useful for the evaluation of DDI studies. The model can be an aid in evaluating DDI studies for compounds with a long elimination half-life, especially when the inhibitor cannot be administered over a sufficient period. Additionally, the population model-based approach may allow simplification of the design and the analysis and interpretation of safety and efficacy findings in DDI studies.

  • A Quantitative Enterohepatic Circulation Model
    Clinical Pharmacokinetics, 2009
    Co-Authors: Thorsten Lehr, Dirk Trommeshauser, Hans Guenter Schaefer, Alexander Staab, Christiane Tillmann, Charlotte Kloft
    Abstract:

    Background and Objective Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t_1/2). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of Tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of Tesofensine and meloxicam to various extents. Methods Two studies were investigated retrospectively for model development and model evaluation. Twentyone healthy subjects received a single 6-hour infusion of Tesofensine (0.3, 0.6, 0.9, 1.2 mg) in a double-blind, randomized, placebo-controlled, single rising-dose study. Twelve healthy subjects were treated in a randomized, crossover study with meloxicam 30 mg as a single dose given intravenously (bolus) either alone or concomitantly with cholestyramine. The EHC model was developed based on data from the Tesofensine study, where EHC is suspected. Model evaluation was performed with data from the meloxicam trial. Modelling and simulation analyses were performed using the software programs NONMEM, SAS and Berkeley Madonna. Results Plasma concentration-time profiles of Tesofensine were best described by a three-compartment model (absorption, central and gallbladder) with first-order elimination. The release of the bile compartment was controlled by a sine function model, switching the bile compartment periodically on and off using the actual clock time as the control element. A four-compartment model (absorption, central, peripheral and gallbladder) with first-order elimination and the sine function for gallbladder control described the meloxicam data best. Coadministration of cholestyramine resulted in a predicted 56% withdrawal of meloxicam from the EHC process causing a reduction in the t_1/2 from ∼19 hours to ∼12 hours. Conclusion A quantitative EHC model was successfully developed that was capable of describing the multiple peaks in plasma concentration-time profiles of Tesofensine and meloxicam very well. Additionally, the model successfully quantified the observed results for an interruption of the meloxicam EHC. The model offers an in silico method to support an EHC hypothesis using standard pharmacokinetic data and might help to guide dosing recommendations of compounds undergoing EHC.

Joanne A. Harrold - One of the best experts on this subject based on the ideXlab platform.

  • Serotonergic anti-obesity agents: past experience and future prospects.
    Drugs, 2011
    Co-Authors: Jason C. G. Halford, Emma J. Boyland, Clare L. Lawton, John E. Blundell, Joanne A. Harrold
    Abstract:

    The role of serotonin (5-hydroxytryptamine) in appetite control is long established. Serotonergic manipulations reduce food intake in rodents in a manner consistent with satiety. In humans, drugs such as fenfluramine, dexfenfluramine and sibutramine all reduce energy intake, suppress hunger and enhance satiety. Effects on eating behaviour and subjective sensations of appetite are associated with the weight loss-inducing effects of these treatments. Currently, no appetite-suppressing drugs are approved specifically for the treatment of obesity. However, a new generation of serotonergic drugs have progressed through clinical development. The serotonin 5-HT2C− receptor selective agonist lorcaserin, a drug specifically developed to target satiety without producing the side effect profiles of its predecessors, has been shown to significantly reduce energy intake and body weight. The weight loss produced by lorcaserin appears modest, and behavioural effects, particularly its supposed satiety-enhancing effects, have yet to be characterized. The monoaminergic re-uptake inhibitor Tesofensine has also been shown to produce impressive weight loss in smaller-scale clinical studies. It remains unclear if this drug produces any effects on appetite mediated by serotonin, or whether weight loss is produced largely through enhanced energy expenditure. Evidence indicates that Tesofensine strengthens satiety, but behavioural specificity and psychological side effects remain an issue. The serotonergic system remains a viable target for anti-obesity treatment. In this review, we examine the limited behavioural data available on these two new CNS-acting appetite suppressants.

  • Serotonergic Anti-Obesity Agents
    Drugs, 2011
    Co-Authors: Jason C. G. Halford, Emma J. Boyland, Clare L. Lawton, John E. Blundell, Joanne A. Harrold
    Abstract:

    The role of serotonin (5-hydroxytryptamine) in appetite control is long established. Serotonergic manipulations reduce food intake in rodents in a manner consistent with satiety. In humans, drugs such as fenfluramine, dexfenfluramine and sibutramine all reduce energy intake, suppress hunger and enhance satiety. Effects on eating behaviour and subjective sensations of appetite are associated with the weight loss-inducing effects of these treatments. Currently, no appetite-suppressing drugs are approved specifically for the treatment of obesity. However, a new generation of serotonergic drugs have progressed through clinical development. The serotonin 5-HT_2C− receptor selective agonist lorcaserin, a drug specifically developed to target satiety without producing the side effect profiles of its predecessors, has been shown to significantly reduce energy intake and body weight. The weight loss produced by lorcaserin appears modest, and behavioural effects, particularly its supposed satiety-enhancing effects, have yet to be characterized. The monoaminergic re-uptake inhibitor Tesofensine has also been shown to produce impressive weight loss in smaller-scale clinical studies. It remains unclear if this drug produces any effects on appetite mediated by serotonin, or whether weight loss is produced largely through enhanced energy expenditure. Evidence indicates that Tesofensine strengthens satiety, but behavioural specificity and psychological side effects remain an issue. The serotonergic system remains a viable target for anti-obesity treatment. In this review, we examine the limited behavioural data available on these two new CNS-acting appetite suppressants.

  • Serotonergic Anti-Obesity Agents
    Drugs, 2011
    Co-Authors: Jason C. G. Halford, Emma J. Boyland, Clare L. Lawton, John E. Blundell, Joanne A. Harrold
    Abstract:

    The role of serotonin (5-hydroxytryptamine) in appetite control is long established. Serotonergic manipulations reduce food intake in rodents in a manner consistent with satiety. In humans, drugs such as fenfluramine, dexfenfluramine and sibutramine all reduce energy intake, suppress hunger and enhance satiety. Effects on eating behaviour and subjective sensations of appetite are associated with the weight loss-inducing effects of these treatments. Currently, no appetite-suppressing drugs are approved specifically for the treatment of obesity. However, a new generation of serotonergic drugs have progressed through clinical development. The serotonin 5-HT_2C− receptor selective agonist lorcaserin, a drug specifically developed to target satiety without producing the side effect profiles of its predecessors, has been shown to significantly reduce energy intake and body weight. The weight loss produced by lorcaserin appears modest, and behavioural effects, particularly its supposed satiety-enhancing effects, have yet to be characterized. The monoaminergic re-uptake inhibitor Tesofensine has also been shown to produce impressive weight loss in smaller-scale clinical studies. It remains unclear if this drug produces any effects on appetite mediated by serotonin, or whether weight loss is produced largely through enhanced energy expenditure. Evidence indicates that Tesofensine strengthens satiety, but behavioural specificity and psychological side effects remain an issue. The serotonergic system remains a viable target for anti-obesity treatment. In this review, we examine the limited behavioural data available on these two new CNS-acting appetite suppressants.

  • Pharmacological management of appetite expression in obesity
    Nature Reviews Endocrinology, 2010
    Co-Authors: Jason C. G. Halford, Emma J. Boyland, John E. Blundell, Tim C. Kirkham, Joanne A. Harrold
    Abstract:

    For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT_2C receptor agonist lorcaserin, the monoamine re-uptake inhibitor Tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individual's natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite. Antiobesity drugs are chosen for their ability to suppress food intake or body weight, with little regard for the psychological factors that influence consumption and weight gain. This Review argues that selective pharmacological targeting of specific emotional and motivational processes that govern appetite and eating may improve outcomes for weight reduction and improved self-control over consumption. Traditional antiobesity drug development focuses on weight and obesity-related disease end points, without adequate consideration of behavioral and psychological changes that initiate weight gain or that impede weight management Classical energy homeostasis models emphasize energy regulation systems, but fail to acknowledge key motivational, emotional and behavioral factors that contribute to energy intake and the propensity to gain weight Drug efficacy has been limited, as key behavioral features of appetite have been ignored—namely, hedonic aspects of consumption and the powerful influence of the environment in triggering overeating Pharmaceutical companies are beginning to focus on treatments that combine existing compounds to exploit additive, or supra-additive, actions of separate agents This approach could be advanced by exploiting the specific actions of drugs on distinct components of eating motivation rather than merely emphasizing simple effects on energy intake and body weight Behavioral analysis can isolate drugs that reduce the desire to eat by acting on the processes that initiate, sustain and terminate meals or inhibit consumption