ABSTRACT
Aim
Evaluate ecnoglutide (XW003) effects on rosuvastatin and digoxin pharmacokinetics (PKs) in healthy adults.
Methods
This was an open‐label, single‐sequence crossover Phase 1 study. Eligible participants received rosuvastatin (10 mg, single dose) and digoxin (0.25 mg, single dose) in two periods: Once before subcutaneous treatment with ecnoglutide and once during steady‐state subcutaneous ecnoglutide (1.2 mg). Coadministration effect was assessed via PK parameters of both drugs.
Results
A total of 28 volunteers received at least one dose of study drug. Co‐administration of ecnoglutide did not affect rosuvastatin and digoxin to a clinically relevant degree. For the area under the concentration‐time curve from time zero to infinity, the geometric mean (GM) ratio (with ecnoglutide vs. alone) [90% confidence interval (CI)] was 106% (94%, 120%) for rosuvastatin and 84% (76%, 94%) for digoxin. Additionally, the maximum plasma concentration (C max) of digoxin decreased from 1.39 to 1.31 ng/mL but remained within the therapeutic window. The most common adverse events (AEs) were weight loss and gastrointestinal AEs, which are pharmacologically associated with glucagon‐like peptide‐1 (GLP‐1). No serious AEs were reported. Notably, ecnoglutide treatment led to substantial body weight reduction, with a mean decrease of 11.2% across the 14‐week intervention.
Conclusion
Based on the PK and safety evaluations, ecnoglutide does not cause clinically significant PK interactions with rosuvastatin or digoxin. Consequently, no dose adjustments for rosuvastatin or digoxin are required when ecnoglutide is co‐administered. However, close clinical and plasma monitoring is advised during the coadministration of digoxin, especially in patients with renal impairment.
Keywords: drug–drug interaction, ecnoglutide (XW003), glucagon‐like peptide‐1 analogue, obesity
1. Introduction
Natural glucagon‐like peptide‐1 (GLP‐1) is a peptide hormone secreted by L‐cells of the intestinal mucosa. It stimulates insulin secretion and suppresses glucagon secretion in a glucose‐dependent manner. Studies have confirmed the presence of GLP‐1 receptors (GLP‐1R) in the pancreas, heart, coronary vasculature, kidneys, gastrointestinal tract and brain regions including the hypothalamus and hippocampus. Consequently, GLP‐1 receptor agonists (GLP‐1RAs) exert broad pharmacological effects following receptor activation. Beyond their glucose‐lowering effects, GLP‐1RAs promote satiety, reduce food intake and decrease body weight [1]. Furthermore, they demonstrate beneficial pharmacological actions including cardiovascular protection [2], renoprotection (kidney protection) [3], enhancement of learning and memory coupled with neuroprotection [4], regulation of lipid metabolism [1] and serum uric acid [5].
Endogenous GLP‐1 is primarily inactivated through degradation by dipeptidyl peptidase‐4 (DPP‐4) and renal elimination, resulting in a plasma half‐life of a mere 1–2 min [6]. Ecnoglutide (XW003) is a novel cyclic adenosine monophosphate (cAMP)‐biassed GLP‐1 receptor agonist, featuring two key engineered modifications: 1. A single amino acid substitution at Position 8 (Alanine→Valine), which has been reported to favour cAMP production over β‐arrestin recruitment and renders the peptide less susceptible to degradation by DPP‐4; 2. Acylation of lysine at Position 30, which enhances albumin binding—an effect believed to reduce renal clearance and thereby prolong the peptide's half‐life. At steady state, the half‐life of ecnoglutide ranges from 124 to 138 h [7]. A favourable safety profile and potent efficacy of ecnoglutide have been consistently observed across completed Phase II and Phase III clinical trials in adults with Type 2 diabetes mellitus (T2DM) and in individuals with overweight or obesity [7, 8].
In vitro studies revealed that ecnoglutide exhibits no significant inducing effect on cytochrome‐P450 (CYP450) isoenzymes and demonstrates no substantial inhibitory activity against drug cellular transporters. Consequently, the risk of drug–drug interactions (DDIs) between ecnoglutide and co‐administered medications mediated through these mechanisms is considered low. However, native GLP‐1 receptor agonists are known to delay gastric emptying, which may alter the absorption of concomitantly administered oral medications [9, 10, 11]. Patients with T2DM and overweight/obesity frequently have comorbidities such as cardiovascular disease and dyslipidemia, necessitating concomitant therapies. Additionally, the impact of delayed gastric emptying on drug absorption may vary depending on the Biopharmaceutics Classification System (BCS) class of the co‐administered drug [12]. Rosuvastatin has low solubility and high permeability, and it is indicated for the treatment of hypercholesterolemia [13]. Digoxin is indicated for the treatment of congestive heart failure, atrial flutter, and atrial fibrillation as the most commonly used cardiac glycoside; it exhibits low solubility, low permeability and a narrow therapeutic range, which necessitates careful dosage adjustment in clinical practice [14]. Therefore, digoxin and rosuvastatin were selected as probe drugs to investigate potential PK interactions with ecnoglutide.
2. Methods
2.1. Study Drugs
The investigational medical products (IMP) were all provided by Sciwind Bioscience Ltd. Hangzhou, China, including ecnoglutide injection (2.4 mg/1.2 mL), Rosuvastatin Calcium Tablets (Crestor) and Digoxin Tablets (Lanoxin). Ecnoglutide was administered by abdomen subcutaneous injection; the rest of IMP were orally administrated with 240 mL water.
2.2. Trial Design
This Phase 1, open‐label, single‐sequence study was conducted in Chinese healthy volunteers to evaluate the effect of ecnoglutide injection (1.2 mg) at steady state on the PK parameters of single‐dose oral rosuvastatin and digoxin. This study protocol was approved by the Clinical Trial Ethics Committee of the West China Second University Hospital (Number: Y2023022) and registered with ClinicalTrials.gov (NCT06335134). This study was performed in accordance with the principles and requirements outlined in the Declaration of Helsinki, the Chinese Good Clinical Practice and Chinese National Medical Products Administration guidelines for DDI studies [15]. All participants provided written informed consent before participation in the study.
Participants were administered single doses of rosuvastatin (10 mg) and digoxin (0.25 mg) separately in the absence (Period 1) and presence (Period 2) of steady‐state subcutaneous ecnoglutide (1.2 mg). Participants were orally administered a single dose of rosuvastatin (10 mg) on Day 1, followed by a single oral dose of digoxin on Day 8, with a 7‐day interval between the two doses (based on the elimination half‐life (t 1/2) of rosuvastatin, 11–12 h). Ecnoglutide administration was initiated on Day 14 using a titration regimen: 0.3 mg once weekly for 4 weeks, 0.6 mg once weekly for the next 4 weeks and 1.2 mg once weekly for another 4 weeks to achieve steady state. This steady state was then sustained for an additional 2 weeks. Twenty‐four h after the fifth and sixth administrations of 1.2 mg ecnoglutide, participants were orally administered single doses of rosuvastatin (10 mg) and digoxin (0.25 mg), respectively. PK analyses of the concomitant medications (rosuvastatin and digoxin) were designed to coincide with the approximate time of maximum ecnoglutide concentration. (Figure 1).
FIGURE 1.
Study design. ● for rosuvastatin (10 mg) administration and PK sampling; ▲ for digoxin (0.25 mg) administration and PK sampling; ★ for ecnoglutide administration, PK and ADA sampling; Ecnoglutide administration was initiated on Day 14 using a titration regimen 0.3 mg once weekly for 4 weeks, 0.6 mg once weekly for the next 4 weeks and 1.2 mg once weekly for another 4 weeks to achieve steady state.
Blood sampling for the assessment of rosuvastatin and digoxin concentrations was performed at predose and at post‐dose time points up to 72 and 120 h, respectively. This sampling was conducted both when the two drugs were administered alone and when they were co‐administered with ecnoglutide. Blood sampling for ecnoglutide was also conducted during the administration (Figure 1).
Participants were to fast at least 10 h before rosuvastatin and digoxin administration. They must refrain from water 1 h before and 2 h after drug administration, and from food for 4 h after drug administration.
2.3. Participants
Eligible participants were males, non‐pregnant and non‐lactating females, aged 18–45 years, body weight ≥ 50 kg and body mass index 20.0–30.0 kg/m2. All participants had to use highly effective contraception since screening to 3 months after finishing the study. Exclusion criteria were any medical history, clinical or laboratory findings or lifestyle factors that would increase participant risk or affect results interpretation.
2.4. Study Objectives and Endpoint
The primary objective was to evaluate the effect of ecnoglutide on the exposure of single‐dose rosuvastatin or digoxin, respectively. The PK parameters, including maximum drug concentration (C max), time to maximum drug concentration (t max), terminal half‐life (t 1/2), area under the curve (AUC) and so forth, were evaluated. The primary endpoints were assessed without and with ecnoglutide treatment, focusing on the AUC from time zero to infinity (AUC0–inf) of rosuvastatin and digoxin. The secondary endpoints included other PK parameters of rosuvastatin and digoxin: AUC from time zero to the last measurable concentration (AUC0–last), C max, t max, t 1/2, apparent oral clearance (CL/F), apparent volume of distribution during the terminal phase (Vz/F) and terminal elimination rate constant (λz); as well as steady‐state PK parameters of ecnoglutide: AUC0–last, AUC0–inf, C max, t 1/2, t max, minimum drug concentration (Cmin), average drug concentration (Cavg), CL/F, Vz/F and degree of fluctuation (DF). Safety and tolerability were also evaluated.
2.5. Blood Sampling and Analysis
For both Period 1 and Period 2, blood samples for PK analysis of rosuvastatin were collected from pre‐dose (0 h), 0.5, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 14, 16, 24, 36, 48 and 72 h after dosing, resulting in a total of 20 PK sampling points per period; blood samples for PK analysis of digoxin were collected before dosing (0 h), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 24, 48, 72, 96 and 120 h after dosing, with 18 PK sampling points per period. Blood samples for PK analysis of ecnoglutide were taken pre‐dose and during the treatment.
The plasma concentrations of rosuvastatin, digoxin and ecnoglutide were quantified using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods. The lower limits of quantification (LLOQ) were 0.05 ng/mL for rosuvastatin and digoxin, and 2.00 ng/mL for ecnoglutide.
2.6. Safety and Tolerability Assessments
Safety and tolerability assessments included adverse events (AEs) observed throughout the study, physical examinations, vital signs, laboratory tests (haematology, biochemistry, coagulation function, thyroid function, calcitonin and urinalysis), 12‐lead electrocardiograms (ECGs) and anti‐drug antibodies (ADA). All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology, version 26.1. The severity of AEs was graded in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
2.7. Statistical Analysis
Based on a 2 one‐sided test with α = 0.05 and β = 0.1, the intra‐individual coefficients of variation for the single‐dose AUC of rosuvastatin and digoxin are no greater than 17% and 18%, respectively. With the assumption that the GM ratio (GMR) of AUC0–inf under co‐administration with and without ecnoglutide falls within 0.95–1.05, and the 90% confidence interval lies within 80%–125%, the calculated sample size is 20 participants. Considering the relatively long study duration and an anticipated dropout rate of ~30%, the planned sample size is 28 participants.
The statistical analysis datasets were categorised into the Safety Dataset (SS), Full Analysis Set (FAS), Pharmacokinetic Concentration Set (PKCS) and Pharmacokinetic Parameter Set (PKPS) (Table S1).
PK parameters were calculated via non‐compartmental analysis (Phoenix WinNonlin version 8.3; Certara USA Inc.) and included the following: C max, t max, AUC0‐inf, percentage of extrapolated AUC (%AUCextrap), t 1/2, CL/F, Vz/F and CLr. Plasma PK parameters for multiple doses included parameters have mentioned at steady‐state, such as C max,ss, AUC0‐inf,ss, AUC0‐last,ss, t ½,ss, CL/F ss, Vz/F ss, besides, C min,ss, C avg,ss and degree of fluctuation, explanation of each parameter are shown in Table S2.
To evaluate the potential effect of ecnoglutide on the PKs of rosuvastatin and digoxin, AUC0‐inf, AUC0‐last and maximum plasma concentration (C max) were analysed using mixed‐effects models. The GM ratio (GMR; defined as the parameter value with ecnoglutide vs. without ecnoglutide) and its corresponding 90% confidence interval (90% CI) were calculated for each parameter, respectively.
3. Results
3.1. Participants
Twenty‐nine participants were enrolled in the study, and one withdrew before any IMP administration. Twenty‐eight participants accepted IMP administration; one of them withdrew before the first ecnoglutide injection due to the participant's own decision. Twenty‐seven participants completed the study without any major protocol deviations (Figure S1). Demographic and baseline characteristics are shown in Table 1.
TABLE 1.
Summary of demographic characteristics based on the FAS.
| Characteristics | Values (N = 28) |
|---|---|
| Mean age [min, max], years | 30.6 [21, 43] |
| Sex, n (%) | |
| Male | 12 (42.86) |
| Female | 16 (57.14) |
| Race, n (%) | |
| Asian | 28 (100) |
| Mean height [min, max], cm | 161.69 [150.6, 179.0] |
| Mean weight [min, max], kg | 70.94 [59.0, 87.9] |
| Mean BMI [min, max], kg/m2 | 27.08 [25.1, 30.0] |
| Glycated haemoglobin [min, max], % | 5.03 [4.30, 6.30] |
Abbreviations: BMI, body mass index; FAS, full analysis set.
3.2. Descriptive Analysis of Rosuvastatin, Digoxin and Ecnoglutide Plasma Concentration
Based on PKCS with or without ecnoglutide, for rosuvastatin peak concentrations (C max) were reached at approximately 4 h post‐dose (t max). By 72 h post‐dose, plasma concentrations in some participants fell below the LLOQ; over 90% of participants, plasma concentrations were below 5% of the C max (Figure 2A); For digoxin, C max were reached at ~1.5 h post‐dose (t max). At around t max, digoxin concentrations were lower with ecnoglutide coadministration compared to administration without ecnoglutide, although all values remained above the efficacy‐related threshold (0.5 ng/mL). Plasma concentrations became comparable between periods by 2.5 h post‐dose. By 120 h post‐dose, concentrations in the majority of participants fell below the LLOQ (Figure 2B). Plasma concentrations of ecnoglutide injection were below the LLOQ prior to the first administration. Steady state was achieved after the fourth administration of the 1.2 mg ecnoglutide injection dose. Plasma concentrations approached the LLOQ at 840 h following the final administration (Figure 3).
FIGURE 2.
Mean plasma concentration‐time profiles of (A) rosuvastatin: Single 10 mg dose alone (unfilled circles, dashed line) versus with ecnoglutide co‐administration (filled circles, solid line). (B) digoxin: Single 0.25 mg dose alone (unfilled circles, dashed line) versus with ecnoglutide co‐administration (filled circles, solid line). (C) digoxin single dose versus with ecnoglutide co‐administration profile truncated at 12 h.
FIGURE 3.
Arithmetic mean plasma concentration‐time profiles of ecnoglutide at steady‐state with titration dosing regimen.
3.3. PK Parameters Analysis
All PK parameters analysis were conducted within PKPS. The GMR and its 90% CI for rosuvastatin AUC0–inf when co‐administered with ecnoglutide compared to rosuvastatin administered alone was 106% (94%, 120%). This GMR 90% CI was entirely contained within the pre‐specified no‐effect boundaries of 80%–125%. The GM values of rosuvastatin C max following administration of rosuvastatin alone and co‐administered with ecnoglutide were 13.16 and 13.43 ng/mL, respectively; the GMR (rosuvastatin + ecnoglutide/rosuvastatin alone) and its 90% CI were 102% (90%, 116%). Both the GMR and its 90% CI fell entirely within the pre‐specified no‐effect boundaries of 80%–125%. The GM values of rosuvastatin AUC0‐last following administration of rosuvastatin alone and co‐administered with ecnoglutide were 123.03 and 129.75 h ng/mL, respectively; the GMR (rosuvastatin + ecnoglutide/rosuvastatin alone) and its 90% CI were 105% (93%, 119%). Both the GMR and its 90% CI were entirely contained within the pre‐specified no‐effect boundaries of 80%–125%, therefore indicating no significant PK interaction effect.
Compared to digoxin administered alone, co‐administration of ecnoglutide with digoxin resulted in a GMR (digoxin + ecnoglutide/digoxin alone) for digoxin AUC0–inf of 84% (76%, 94%). This represents a relative reduction of 16% in digoxin AUC0–inf. The GM values of digoxin C max following administration of digoxin alone and co‐administered with ecnoglutide injection were 1.39 and 1.13 ng/mL, respectively; the GMR (digoxin + ecnoglutide/digoxin alone) and its 90% CI were 81% (68%, 97%). This represents a relative reduction of 19% in digoxin C max. The GM values of digoxin AUC0–last following administration of digoxin alone and co‐administered with ecnoglutide were 17.13 and 13.64 h ng/mL, respectively; the GMR (digoxin + ecnoglutide/digoxin alone) and its 90% CI were 80% (69%, 91%). This represents a relative reduction of 20% in digoxin AUC0–last (Table 2).
TABLE 2.
Statistical analysis of pharmacokinetic parameters.
| Analyse | Parameter | With ecnoglutide | Without ecnoglutide | Ratio of geometric LS mean a (90% CI) with ecnoglutide/without ecnoglutide | ||
|---|---|---|---|---|---|---|
| N | Geometric LS mean | N | Geometric LS mean | |||
| Rosuvastatin | AUC0‐inf (h ng/mL) | 27 | 133.65 | 28 | 125.70 | 106.32 (94.35, 119.80) |
| AUC0‐last (h ng/mL) | 27 | 129.75 | 28 | 123.03 | 105.46 (93.47, 119.00) | |
| C max (ng/mL) | 27 | 13.43 | 28 | 13.16 | 102.03 (89.58, 116.22) | |
| Digoxin | AUC0‐inf (h ng/mL) | 27 | 17.63 | 28 | 20.87 | 84.48 (75.54, 94.46) |
| AUC0‐last (h ng/mL) | 27 | 13.64 | 28 | 17.13 | 79.60 (69.33, 91.39) | |
| C max (ng/mL) | 27 | 1.13 | 28 | 1.39 | 81.49 (68.21, 97.36) | |
Abbreviations: AUC0‐inf, area under the concentration‐time curve extrapolated to infinity; AUC0‐last, area under the concentration‐time curve until the last measurable concentration; CI, confidence interval; C max, maximum observed concentration: LS mean, Least Squares mean.
The interval used in the assessment of 90% CI of geometric ratios for all parameters was 80%–125%.
Other secondary PK parameters analysis for rosuvastatin versus rosuvastatin + ecnoglutide, digoxin versus digoxin + ecnoglutide and multi‐dose of ecnoglutide are shown in Tables S3–S5.
3.4. Safety and Tolerability
A total of 184 AEs were reported among all 28 enrolled participants (100.0%); notably, no Grade > 3 AEs, AEs leading to study drug discontinuation, AEs leading to study withdrawal, SAEs or deaths occurred. The distribution of AEs across treatment phases was as follows: Eight AEs occurred in 6 participants (21.4%) during rosuvastatin alone administration, three AEs in three participants (10.7%) during digoxin alone administration, 131 AEs in all 28 participants (100.0%) during ecnoglutide administration, 30 AEs in 14 participants (51.9%) during co‐administration of ecnoglutide with rosuvastatin and 12 AEs in 10 participants (37.0%) during co‐administration of ecnoglutide with digoxin. The majority of AEs during all phases were Grade 1 (mild) in severity. By the end of the study, the majority of AEs (88.6%, 163/184) had resolved, while the remaining 21 unresolved AEs all pertained to weight decrease. Overall, 150 AEs occurring in all 28 participants (100.0%) were assessed as treatment‐related to ecnoglutide injection, and most of them were gastrointestinal AEs, including one Grade 3 AE (elevated lipase) experienced by one participant (3.6%) and recovered without any treatment. The AEs summarised by System Organ Class (SOC) are listed in Table 3.
TABLE 3.
Adverse events summarised by system organ class.
| Rosuvastatin (N = 28) | Digoxin (N = 28) | Ecnoglutide (N = 28) | Rosuvastatin+ ecnoglutide (N = 27) | Digoxin+ ecnoglutide (N = 27) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N (%) | E | N (%) | E | N (%) | E | N (%) | E | N (%) | E | |
| AEs | 6 (21.43) | 8 | 3 (10.71) | 3 | 28 (100.00) | 131 | 14 (51.85) | 30 | 10 (37.04) | 12 |
| Investigations | 6 (21.43) | 8 | 3 (10.71) | 3 | 27 (96.43) | 35 | 9 (33.33) | 12 | 8 (29.63) | 8 |
| Gastrointestinal disorders | 0 (0.00) | 0 | 0 (0.00) | 0 | 18 (64.29) | 64 | 9 (33.33) | 16 | 1 (3.70) | 2 |
| Metabolism and nutrition disorders | 0 (0.00) | 0 | 0 (0.00) | 0 | 10 (35.71) | 22 | 0 (0.00) | 0 | 0 (0.00) | 0 |
| Infections and infestations | 0 (0.00) | 0 | 0 (0.00) | 0 | 5 (17.86) | 5 | 0 (0.00) | 0 | 2 (7.41) | 2 |
| Nervous system disorders | 0 (0.00) | 0 | 0 (0.00) | 0 | 1 (3.57) | 5 | 1 (3.70) | 1 | 0 (0.00) | 0 |
| Cardiac disorders | 0 (0.00) | 0 | 0 (0.00) | 0 | 0 (0.00) | 0 | 1 (3.70) | 1 | 0 (0.00) | 0 |
Abbreviations: E, number of events; N, number of participants.
All participants had blood samples collected for ADA analysis within 1 h prior to the first dose and at 840 h (±24 h) following the final administration of ecnoglutide injection, all of which yielded negative results.
Body weight was monitored under fasting conditions in the morning at screening period, and Day 1, Day 8, Day 14, Day 42, Day 70, Day 98, Day 105, Day 111 and Day 140 of the study. The mean weight change from Day 14 (pre‐first ecnoglutide dose) to Day 105 (last ecnoglutide dose visit) was 7.9 kg, corresponding to an 11.2% reduction (Figure 4). Furthermore, treatment with ecnoglutide was associated with improvements in cardiovascular risk factors, including triglycerides, total cholesterol, fasting serum glucose and uric acid (Figure S2).
FIGURE 4.
Body weight changes during study.
4. Discussion
This study employed an open‐label, single‐sequence design, aiming to evaluate the effects of ecnoglutide on two commonly used oral drugs: rosuvastatin and digoxin. The time point for PK analysis of concomitant medications was set at 24 h after receiving ecnoglutide to maximise the detection of potential DDIs. The validity of this time point was verified by the administration of ecnoglutide in the trial.
In the Phase III clinical program for T2DM, the target maintenance doses of ecnoglutide were 0.6 mg (titrated upward from 0.3 mg every 4 weeks, with an 8‐week time to reach the maintenance dose) and 1.2 mg (with a 12‐week titration period) [16]. For weight management, the target doses were 1.2 (12‐week titration), 1.8 (16‐week titration) and 2.4 mg (20‐week titration) [7, 8]. Given the extended titration periods required to reach these maintenance doses and considering clinical practicality, this DDI study evaluated the impact of ecnoglutide on the PKs of digoxin and rosuvastatin after steady‐state was achieved at the 1.2 mg dose, a level common to both the T2DM and weight management indications.
Administration of ecnoglutide injection did not alter the AUC or C max of a single 10 mg dose of rosuvastatin. These findings indicate that there is no clinically significant PK interaction between ecnoglutide and rosuvastatin. Consequently, no dose adjustment of rosuvastatin is required in clinical practice, showing the same conclusion with other GLP‐1RA, such as semaglutide [17] and dulaglutide [18].
Coadministration of ecnoglutide injection with digoxin resulted in mild reductions in the mean AUC and C max of digoxin, along with a delayed t max, compared to digoxin administration alone. Digoxin is a poorly soluble and permeable drug. Theoretically, delayed gastric emptying could increase the time available for drug dissolution, potentially increasing drug exposure. However, reference studies with other GLP‐1 RA show variability: Coadministration with liraglutide injection reduced digoxin AUC and C max by 16% and 31%, respectively [19]; coadministration with albiglutide resulted in no change in AUC but an 11% increase in C max [20] and coadministration with semaglutide showed no change in AUC or C max [17]. In healthy Chinese adults, PB‐119 (PEX‐168), another long‐acting GLP‐1 receptor agonist, did not affect digoxin PKs, with all primary PK parameters remaining within the predefined bioequivalence range [21]. Such variability may be attributed to the substantial inter‐individual differences in the rate and extent of digoxin absorption and the significant influence of confounding factors. In this study, the mean C max values of digoxin with and without ecnoglutide coadministration were 1.31 and 1.45 ng/mL, respectively. These levels remain within the established therapeutic range according to prescribing information of digoxin, indicating that the bioavailability of digoxin was not significantly impacted. These results support the clinical coadministration of digoxin and ecnoglutide without necessitating dose adjustment. Nevertheless, digoxin's narrow therapeutic window makes it a leading pharmacological cause of hospital admissions due to toxicity. Accordingly, we recommend measuring drug levels when co‐treatment with ecnoglutide, particularly in patients with renal impairment, who are at risk of drug accumulation to toxic levels.
Over the ~16‐week intervention period and 5‐week follow‐up period of this study, the most frequently reported AEs involved the gastrointestinal system (including diarrhoea, nausea, vomiting, abdominal distension, etc.) and decreased appetite. These were predominantly mild, of short duration, and resolved without intervention in most cases. Overall, the safety profile of ecnoglutide injection, whether administered alone or concomitantly with rosuvastatin or digoxin, was consistent with findings from previous studies and the established safety profile of other GLP‐1 RAs.
Notably, ecnoglutide treatment led to substantial body weight reduction, with a mean decrease of 11.2% across the 14‐week intervention. Furthermore, the improvements in several cardiovascular risk factors, including triglycerides, total cholesterol, fasting serum glucose and uric acid observed with ecnoglutide treatment, suggest potential cardiometabolic benefits that warrant further investigation.
This study has several limitations. First, the drug interaction assessments for rosuvastatin and digoxin were based on single‐dose administration, which may not fully capture potential interactions under steady‐state conditions. Second, the relatively small sample size of healthy volunteers may limit the generalisability of the findings. Additionally, given that ecnoglutide requires gradual upward dose titration from lower starting doses, it was evaluated at a steady‐state dose of 1.2 mg rather than the maximum clinical maintenance dose (2.4 mg for weight management). Nevertheless, such a design is customary for this type of study. In addition, the 24‐h post‐dose PK assessment was selected because it falls within the possible t max window of ecnoglutide observed in Phase 1 studies [22].
5. Conclusion
Based on the PK and safety evaluations, ecnoglutide does not affect any clinically significant PK interactions with rosuvastatin or digoxin. Consequently, no dose adjustments for rosuvastatin or digoxin are required when ecnoglutide is coadministered with those drugs. Patients receiving digoxin and another GLP‐1 receptor agonist should have digoxin concentration in plasma closely monitored. Based on the PK and safety evaluations, the observed changes in rosuvastatin and digoxin exposure following coadministration with ecnoglutide are not expected to be clinically meaningful. However, given the narrow therapeutic index of digoxin, close clinical and plasma concentration monitoring should still be considered during coadministration, particularly in patients with renal impairment, although the observed digoxin concentrations remained within the therapeutic range in this study.
Author Contributions
Q.Y., S.F., L.C., L.G., Q.Z., L.Y., Y.L., R.L. and M.Y.: design; F.L., C.D., Z.C., Q.Z., W.G., D.D., F.H., X.L., Y.H., S.S. and W.S.: data collection and participants management; F.L. and Q.Z.: writing original draft. All authors reviewed the manuscript critically and approved the submitted version. The authors confirm that the Principal Investigator for this paper is Yu Qin and that she had direct clinical responsibility for patients.
Funding
This study was funded by Sciwind Bioscience Ltd.
Conflicts of Interest
Lei Guan, Qing Zheng, Liu Yang, Yao Li, Rui Liu and Ming Yang are employees and shareholders of Hangzhou Sciwind Biosciences Co. Ltd. The rest of the authors are all staff of the National Drug Clinical Trial Institution of West China Second University Hospital, who declare no conflicts of interest related to this publication.
Supporting information
Figure S1: Participant disposition.
Figure S2: Violin plots of relevant indicators before and after ecnoglutide.
Table S1: Definitions of each statistical analysis datasets.
Table S2: Explanation of PK parameters.
Table S3: Rosuvastatin plasma PK parameters with and without coadministration of 1.2 mg ecnoglutide.
Table S4: Digoxin plasma PK parameters with and without the coadministration of 1.2 mg ecnoglutide.
Table S5: Steady‐state PK parameters of 1.2 mg ecnoglutide.
Table S6: The PK sampling schedule.
Table S7: AEs summarised by SOC and PT.
Supplement 1: Statistical method.
Supplement 2: Information on bioanalytical method.
Li F., Du C., Yu Q., et al., “Effect of a Novel GLP‐1 Analogue Ecnoglutide on the Pharmacokinetics of Rosuvastatin and Digoxin in Healthy Participants,” Diabetes, Obesity and Metabolism 28, no. 9 (2026): 8128–8135, 10.1111/dom.70880.
Handling Editor: Richard Donnelly
Contributor Information
Qin Yu, Email: yuqin@scu.edu.cn.
Lei Guan, Email: lei.guan@sciwindbio.com.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author (NA), upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Participant disposition.
Figure S2: Violin plots of relevant indicators before and after ecnoglutide.
Table S1: Definitions of each statistical analysis datasets.
Table S2: Explanation of PK parameters.
Table S3: Rosuvastatin plasma PK parameters with and without coadministration of 1.2 mg ecnoglutide.
Table S4: Digoxin plasma PK parameters with and without the coadministration of 1.2 mg ecnoglutide.
Table S5: Steady‐state PK parameters of 1.2 mg ecnoglutide.
Table S6: The PK sampling schedule.
Table S7: AEs summarised by SOC and PT.
Supplement 1: Statistical method.
Supplement 2: Information on bioanalytical method.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author (NA), upon reasonable request.