The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs.

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study.

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts.

Ultra rapid lispro (Lyumjev®) shortens time to recovery from hyperglycaemia compared to Humalog® in individuals with type 1 diabetes on continuous subcutaneous insulin infusion.

Aims: To compare the time to hyperglycaemia recovery after ultra rapid lispro (URLi; Lyumjev®) versus Humalog in a randomized, double-blind crossover study.

Materials And Methods: Thirty-two adults with type 1 diabetes on continuous subcutaneous insulin infusion participated in two periods: each period included hyperglycaemia induced by a missed mealtime bolus (day 1) and by suspension of basal insulin delivery (day 2). When hyperglycaemia [plasma glucose (PG) >240 mg/dl] occurred, a correction bolus of URLi or Humalog was given and time to hyperglycaemia recovery (PG = 140 mg/dl), pharmacokinetics and glucodynamics were compared.

Ultra rapid lispro showed greater reduction in postprandial glucose versus Humalog in children, adolescents and adults with type 1 diabetes mellitus.

Aim: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D).

Materials And Methods: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.

Therapeutic Protein Drug Interactions: A White Paper From the International Consortium for Innovation and Quality in Pharmaceutical Development.

Typically, therapeutic proteins (TPs) have a low risk for eliciting meaningful drug interactions (DIs). However, there are select instances where TP drug interactions (TP-DIs) of clinical concern can occur. This white paper discusses the various types of TP-DIs involving mechanisms such as changes in disease state, target-mediated drug disposition, neonatal Fc receptor (FcRn), or antidrug antibodies formation.

Evaluation of the Pharmacokinetic Profile of Ultra Rapid Lispro Administered Subcutaneously at Different Injection Sites.

Purpose: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site.

Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects.

Purpose: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects.

Methods: This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects.

Bioequivalence of Ultra Rapid Lispro (URLi) U100 and U200 Formulations in Healthy Subjects.

Introduction: Ultra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations.

Methods: This phase 1, randomized, two-sequence, four-period, double-blind, replicate crossover study was conducted in 68 healthy subjects.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Background And Objective: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).

Methods: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog (Lispro) in Younger Adults and Elderly Patients with Type 1 Diabetes Mellitus: A Randomised Controlled Trial.

Background: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog in patients with type 1 diabetes mellitus (T1DM).

Methods: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM.

Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: A phase 1 randomized, crossover study.

Aims: To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D).

Materials And Methods: This was a randomized, double-blind, four-period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal.

Disease-Drug Interactions in Inflammatory States via Effects on CYP-Mediated Drug Clearance.

The human inflammatory response can result in the alteration of drug clearance through effects on drug-metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)-mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α-1-acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.

LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles.

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib.

Nonclinical pharmacology and toxicology of the first biosimilar insulin glargine drug product (BASAGLAR/ABASAGLAR) approved in the European Union.

Basaglar/Abasaglar (Lilly insulin glargine [LY IGlar]) is a long-acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union-sourced SA IGlar (EU-SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin-like growth factor-1 (IGF-1) receptors, or in assays of functional or de novo lipogenic activity.

Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus.

Aims: LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM).

Materials And Methods: This was a randomized, double-blind, single-dose, two-period, crossover study.

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies.

Objective: LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union- and US-approved versions of IGlar.

Research Design And Methods: These were three single-site, randomized, double-blind, two-treatment, four-period, crossover, euglycemic clamp studies.

Assessment of fetal exposure risk following seminal excretion of a therapeutic IgG4 (T-IgG4) monoclonal antibody using a rabbit model.

Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (three orders of magnitude lower than IV administration).

Structure-activity relationships of SERMs optimized for uterine antagonism and ovarian safety.

Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.

Androgen dependent mammary gland virilism in rats given the selective estrogen receptor modulator LY2066948 hydrochloride.

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland.