Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [14C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [14C]-Tirzepatide was prepared by incorporating four 14C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 µCi of [14C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg-1 (133 µCi/kg) of [14C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg-1 (20 µCi/kg) of [14C]-tirzepatide. Following a single SC dose of [14C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, ß-oxidation of the C20 diacid moiety, and amide hydrolysis. ClinicalTrials.gov identifier: NCT 04,311,424.

Role of Clinical Pharmacology in Diversity and Inclusion in Global Drug Development: Current Practices and Industry Perspectives: White Paper.

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements.

Effects of Tirzepatide vs Semaglutide on ß-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.

CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. DESIGN: A 28-week double-blind, randomized, placebo-controlled trial. SETTING: Two clinical research centers in Germany. PATIENTS: Patients with type 2 diabetes treated with metformin. INTERVENTIONS: Tirzepatide 15 mg, semaglutide 1 mg, placebo. MAIN OUTCOME MEASURES: Glycemic control, model-derived ß-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), ß-cell glucose (ß-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved ß-CG responsiveness. MMTT-derived ß-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSIONS: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.

Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.

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.

Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial.

Importance: Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen. Objective: To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin. Design, Setting, and Participants: This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands. Interventions: The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher. Main Outcomes and Measures: Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers. Results: Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed. Conclusion: Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT04472676.

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

INTRODUCTION: To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Chinese patients with type 2 diabetes (T2D). METHODS: In this phase 1, double-blind, placebo-controlled, multiple dose study, patients were randomized into one of two cohorts to receive once-weekly subcutaneous tirzepatide or placebo. The initial tirzepatide dose in both cohorts was 2.5 mg, which was increased by 2.5 mg every 4 weeks to a maximum final dose of 10.0 mg at week 16 (Cohort 1) or 15.0 mg at week 24 (Cohort 2). The primary outcome was the safety and tolerability of tirzepatide. RESULTS: Twenty-four patients were randomized (tirzepatide 2.5-10.0 mg: n = 10, tirzepatide 2.5-15.0 mg: n = 10, placebo: n = 4); 22 completed the study. The most frequently reported treatment-emergent adverse events (TEAEs) among patients receiving tirzepatide were diarrhea and decreased appetite; most TEAEs were mild and resolved spontaneously with no serious adverse events reported in the tirzepatide groups and one in the placebo group. The plasma concentration half-life of tirzepatide was approximately 5-6 days. Mean glycated hemoglobin (HbA1c) decreased over time from baseline in the 2.5-10.0 mg (- 2.4%) and 2.5-15.0 mg (- 1.6%) tirzepatide groups, at week 16 and week 24, respectively, but remained steady in patients receiving placebo. Body weight decreased from baseline by - 4.2 kg at week 16 in the tirzepatide 2.5-10.0 mg group and by - 6.7 kg at week 24 in the 2.5-15.0 mg group. Mean fasting plasma glucose levels fell from baseline by - 4.6 mmol/L in the tirzepatide 2.5-10.0 mg group at week 16 and by - 3.7 mmol/L at week 24 in the tirzepatide 2.5-15.0 mg group. CONCLUSIONS: Tirzepatide was well tolerated in this population of Chinese patients with T2D. The safety, tolerability, PK, and PD profile of tirzepatide support once-weekly dosing in this population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04235959.