المؤلفون: Karen Schneck, Shweta Urva

المصدر: CPT: Pharmacometrics & Systems Pharmacology, Vol 13, Iss 3, Pp 494-503 (2024)

مصطلحات موضوعية: Therapeutics. Pharmacology, RM1-950

الوصف: Abstract Tirzepatide is a first‐in‐class glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population‐based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well‐described by a two‐compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half‐life of tirzepatide was ~5 days and enabled sustained exposure with once‐weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2163-8306Test

الوصول الحر: https://doaj.org/article/fb3b81682750428da2ed990b59795c31Test

المؤلفون: Shweta Urva, Joshua A Levine, Karen Schneck, Cheng Cai Tang

مصطلحات موضوعية: Biochemistry, Genetics, Physiology, Pharmacology, Science Policy, Computational Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, type 2 diabetes, glycated hemoglobin, body weight, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, tirzepatide

الوصف: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions. Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change ...

العلاقة: https://figshare.com/articles/journal_contribution/Model-based_simulation_of_glycaemic_effect_and_body_weight_loss_when_switching_from_semaglutide_or_dulaglutide_to_once_weekly_tirzepatide/25289189Test

الإتاحة: https://doi.org/10.6084/m9.figshare.25289189.v1Test
https://figshare.com/articles/journal_contribution/Model-based_simulation_of_glycaemic_effect_and_body_weight_loss_when_switching_from_semaglutide_or_dulaglutide_to_once_weekly_tirzepatide/25289189Test

المؤلفون: Dipak R. Patel, Shweta Urva, Stephen Ho, Cody J. Buckman, Yanfei Ma, Jean Lim, Sean E. Sissons, Mary S. Zuniga, Diane Philips, Karen Cox, Daniel J. Dairaghi

المصدر: Clinical and Translational Science, Vol 14, Iss 3, Pp 1037-1048 (2021)

مصطلحات موضوعية: Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270

الوصف: Abstract LY2775240 is a highly selective, potent and orally‐administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNFα production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2‐part first‐in‐human randomized study, a wide dose range of LY2775240 was safely evaluated and found to be well‐tolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was well‐characterized, with a half‐life that can support once‐a‐day dosing. An ex vivo pharmacodynamic (PD) assay demonstrated dose‐dependent PDE4 target engagement as assessed by reduction in TNFα production. A 20 mg dose of LY2775240 led to near‐maximal TNFα inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30 mg) in the crossover, second part of this study. The 20 mg dose of LY2775240 demonstrated sustained maximal (50%–80%) inhibition of TNFα over all timepoints over the 24‐h duration. The comparator apremilast achieved peak inhibition of ~ 50% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Phosphodiesterase 4 (PDE4) inhibitors, such as apremilast, are currently approved to treat autoimmune disorders, such as psoriasis. LY2775240 is an oral PDE4 inhibitor being developed for treatment of a variety of inflammatory disorders. The degree of enzymatic inhibition achieved by PDE4 inhibitors clinically is poorly understood. WHAT QUESTION DID THIS STUDY ADDRESS? This study investigated single ascending doses of LY2775240, a highly selective oral PDE4 inhibitor, in healthy subjects. LY2775240 was well‐tolerated over the dose range evaluated, and pharmacokinetic/pharmacodynamic (PD) profiles were well‐characterized. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study evaluated different doses of LY2775240 and subsequently compared a selected LY2775240 dose with the clinical dose of apremilast with an ex vivo assay. This information builds a connection between target engagement and clinical efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposure‐response relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1752-8054Test; https://doaj.org/toc/1752-8062Test

الوصول الحر: https://doaj.org/article/26338cb3724a46be895644ae7734a730Test

المؤلفون: Tim Heise, J. Hans DeVries, Shweta Urva, Jing Li, Edward J. Pratt, Melissa K. Thomas, Kieren J. Mather, Chrisanthi A. Karanikas, Julia Dunn, Axel Haupt, Zvonko Milicevic, Tamer Coskun

المصدر: Diabetes Care. 46:998-1004

مصطلحات موضوعية: Advanced and Specialized Nursing, Endocrinology, Diabetes and Metabolism, Internal Medicine

الوصف: OBJECTIVE To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::48517387ad5d00f605bd3c125d750b3dTest
https://doi.org/10.2337/dc22-1710Test

المؤلفون: Tamer Coskun, Kyle W. Sloop, Corina Loghin, Jorge Alsina-Fernandez, Shweta Urva, Krister B. Bokvist, Xuewei Cui, Daniel A. Briere, Over Cabrera, William C. Roell, Uma Kuchibhotla, Julie S. Moyers, Charles T. Benson, Ruth E. Gimeno, David A. D'Alessio, Axel Haupt

المصدر: Molecular Metabolism, Vol 18, Iss , Pp 3-14 (2018)

مصطلحات موضوعية: Internal medicine, RC31-1245

الوصف: Objective: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). Methods: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176. Results: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: −49.12 mg/dL [−78.14, −20.12] and −43.15 mg/dL [−73.06, −13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: −1.75 kg [−3.38, −0.12], −5.09 kg [−6.72, −3.46] and −4.61 kg [−6.21, −3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: −2.62 kg [−3.79, −1.45] and −2.07 kg [−3.25, −0.88], respectively.The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. Conclusions: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity. Keywords: Glucagon-like peptide-1, Glucose-dependent insulinotropic polypeptide, LY3298176, Obesity, Type 2 diabetes mellitus

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877818309001Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/e80aeca8145a4ac5b361969b75b1dc5eTest

المؤلفون: Shweta, Urva, Tamer, Coskun, Mei Teng, Loh, Yu, Du, Melissa K, Thomas, Sirel, Gurbuz, Axel, Haupt, Charles T, Benson, Martha, Hernandez-Illas, David A, D'Alessio, Zvonko, Milicevic

المصدر: The Lancet. 400:1869-1881

مصطلحات موضوعية: Adult, Body Weight, Gastric Inhibitory Polypeptide, General Medicine, Middle Aged, Glucagon, Glucagon-Like Peptide-1 Receptor, Young Adult, Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Glucagon-Like Peptide 1, Receptors, Glucagon, Humans, Obesity, Aged

الوصف: Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study.In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin ABetween Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2·8 mmol/L [90% CI -4·63 to -0·94] for 3 mg; -3·1 mmol/L [-4·91 to -1·22] for 3/6 mg; and -2·9 mmol/L [-4·70 to -1·01] for 3/6/9/12 mg). Placebo-adjusted sHbAIn this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development.Eli Lilly and Company.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1c6fbf9575e306306e92cc4c2bbb96b7Test
https://doi.org/10.1016/s0140-6736Test(22)02033-5

المؤلفون: Francis S. Willard, Jonathan D. Douros, Maria B.N. Gabe, Aaron D. Showalter, David B. Wainscott, Todd M. Suter, Megan E. Capozzi, Wijnand J.C. van der Velden, Cynthia Stutsman, Guemalli R. Cardona, Shweta Urva, Paul J. Emmerson, Jens J. Holst, David A. D’Alessio, Matthew P. Coghlan, Mette M. Rosenkilde, Jonathan E. Campbell, Kyle W. Sloop

المصدر: JCI Insight, Vol 5, Iss 17 (2020)

مصطلحات موضوعية: Therapeutics, Medicine

الوصف: Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/03002ae150b14972b6d0c404574ecbbdTest

المؤلفون: Tim Heise, J Hans DeVries, Shweta Urva, Jing Li, Edward John Pratt, Melissa K. Thomas, Kieren Mather, Julia Dunn, Axel Haupt, Zvonko Milicevic, Tamer Coskun

المصدر: Diabetologie und Stoffwechsel.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::575679ff9692b1e75e6d117a75908a6aTest
https://doi.org/10.1055/s-0043-1767865Test

المؤلفون: Tamer Coskun, Zvonko Milicevic, Axel Haupt, Julia Dunn, Chrisanthi A. Karanikas, Kieren J. Mather, Melissa K. Thomas, Edward J. Pratt, Jing Li, Shweta Urva, J Hans DeVries, Tim Heise

الوصف: OBJECTIVE: To evaluate effects of tirzepatide on body composition, appetite and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N=45), semaglutide 1 mg (N=44) and placebo (N=28) on body weight and composition, appetite, and energy intake were assessed at baseline and Week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared to placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite vs placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-hour energy intake, substrate utilization and energy expenditure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8174afe34e453bf3a6daeece5fa35b3dTest
https://doi.org/10.2337/figshare.21984596.v1Test

المؤلفون: Andrea Bauer, Philippe Berben, Sudhir S. Chakravarthi, Sayantan Chattorraj, Ashish Garg, Betty Gourdon, Tycho Heimbach, Ye Huang, Christopher Morrison, Deepak Mundhra, Ramesh Palaparthy, Pratik Saha, Maxime Siemons, Naveed A. Shaik, Yi Shi, Sara Shum, Naveen K. Thakral, Shweta Urva, Ryan Vargo, Venkat R. Koganti, Stephanie E. Barrett

المصدر: Pharmaceutical Research.

مصطلحات موضوعية: Pharmacology, Organic Chemistry, Pharmaceutical Science, Molecular Medicine, Pharmacology (medical), Biotechnology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::3930deded7f88a1948c914b914796267Test
https://doi.org/10.1007/s11095-022-03391-yTest