Efsubaglutide Alfa

Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects. This study aims to develop a population pharmacokinetic (popPK) model for efsubaglutide alfa to characterize its pharmacokinetic (PK) profile and assess the impact of intrinsic and extrinsic factors.

A popPK model was developed using a nonlinear mixed-effects model (NONMEM) based on 4173 plasma concentration measurements of efsubaglutide alfa from 911 participants, including 36 healthy subjects and 875 patients with T2D, across four clinical trials. These trials involved once-weekly subcutaneous injections of efsubaglutide alfa at doses ranging from 0.375 mg to 9.0 mg, with treatment durations spanning from 1 to 24 weeks. Diagnostic plots, visual predictive checks, nonparametric bootstrap methods, and simulations were employed to validate the model's robustness and performance. Covariates were identified using stepwise covariate modeling.

A two-compartment model with first-order absorption and first-order elimination adequately described the PK characteristics of efsubaglutide alfa. Efsubaglutide alfa exhibited favorable absorption (K_a = 0.0255 per hour) and a relatively large apparent volume of distribution (V₂/F of 14.5 L with relative standard error [RSE] of 3%; V₃/F of 3.01 L). It showed moderate clearance (CL/F of 0.0680 L/h, RSE of 1%, inter-individual variability of 16.6%) and an extended half-life. In subjects with T2D, the geometric mean half-life was estimated between 182 and 215 h across the 1-3 mg dose range, supporting once-weekly or once-every-two-week dosing. Efsubaglutide alfa exposure increased proportionally with dose and remained consistent across studies. Baseline body weight (WT), baseline estimated glomerular filtration rate (eGFR), neutralizing antidrug antibody (Nab), STUDY, and planned dose (ARM) were identified as significant covariates for CL/F, while baseline WT and STUDY influenced V₂/F. Although baseline WT and eGFR affected exposure parameters (AUC_ss, C_max,ss, and C_min,ss), these effects were not clinically significant, suggesting no need for dose adjustment.

The final popPK model, incorporating significant covariates (baseline WT, baseline eGFR, Nab, STUDY, and ARM), provided robust and precise PK parameter estimates, confirming its applicability in both healthy subjects and those with T2D. The minimal and clinically insignificant impact of baseline WT and eGFR on drug exposure supports the conclusion that no dose adjustment is necessary based on these factors. Moreover, the higher absorption rate constant suggests a rapid onset of action, and the extended half-life supports less frequent dosing, potentially improving patient adherence.

The trials were registered at Clinicaltrials.gov (identifiers: NCT03745885, NCT04314622, NCT04994288, and NCT04998032).

We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic effects in type 2 diabetes db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single subcutaneous and intravenous injection(s) in rats and rhesus monkeys, as well as fourconsecutive subcutaneous injections in monkeys.We found the half-life (t1/2) of supaglutide was 39.7 h and 35.8 h at dosing 0.1 mg/kg upon subcutaneous or intravenous administration respectively, in rhesus monkeys. The plasma supaglutide peaked at 8-10 h, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics (Ke) were found to be similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys), whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, a single dose injection of supaglutide markedly decreased the random blood glucose levels that reaching the maxima effects in 14-16 h, gradually recovered and returned to the baseline level approximately after 72 h. ¹²⁵I-supaglutide was found mainly distributed in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but mostly not in bile.Our results show that supaglutide possess linear pharmacokinetic characteristics associated with prolonged hypoglycemic effects inanimals,suggestinga potential weekly dosing therapeutic reagent for the treatment of type 2 diabetes and metabolic diseases.