Population Pharmacokinetics of Survodutide in Subjects with Overweight or Obesity with and without Type 2 Diabetes Mellitus Based on Phase I and Phase II Data
Giovanni Smania (1), Anaïs Glatard (1), Martin Bergstrand (1), Bernhard Schmid (2), Silke Retlich (2), Jan-Georg Wojtyniak (2)
(1) Pharmetheus AB, (2) Boehringer Ingelheim Pharma GmbH & Co. KG
Objectives: Agonists of incretin receptors are increasingly developed as novel treatment options in a range of metabolic diseases. Survodutide is a dual glucagon/glucagon-like peptide 1 receptor agonist resulting in increased energy expenditure, reduced energy intake, and weight loss [1]. The aim of the present analysis was to characterize the population pharmacokinetics (PK) of survodutide based on Phase I and Phase II data.
Methods: The data for this analysis originated from 3 Phase I studies and 2 Phase II studies in patients with obesity with (ClinicalTrials.gov ID: NCT04153929) and without (ClinicalTrials.gov ID: NCT04667377) T2DM. A total of 745 subjects were included in the analysis. PK sampling was rich in Phase I and sparse in Phase II studies. The population analysis was performed using NONMEM version 7.5, while data management and further processing of NONMEM output were performed using R version 3.5.3. Potential covariate-parameter relationships were evaluated using the stepwise covariate model building procedure (SCM) with adaptive scope reduction and stage-wise filtering [2]. The tested covariates included body weight (WT), BMI, percentage fat mass, estimated glomerular filtration rate, race, sex and dose. After finalizing the PK model, the impact of anti-drug antibody (ADA) as both a subject-level and time-varying covariate was evaluated. Covariate effects were visualized on maximum concentration during a dosing interval at steady state (Cmax,ss) and area under the concentration-time curve during a dosing interval at steady state (AUCτ,ss).
Results: The population PK of survodutide was best described by a one-compartment model with first-order absorption and first-order elimination. Inter-individual variability (IIV) terms were included on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), first-order absorption rate constant and residual unexplained variability, with a covariance term between the IIV on CL/F and Vc/F. Among the evaluated covariates, the one with the largest effect was WT. For example, the median AUCτ,ss in a subject of 140 kg was decreased by approximately 35% compared to a 95 kg-subject. After accounting for the WT differences, the typical CL/F in study NCT04667377 was 14% lower than in other studies. As study NCT04667377 is the first phase II study in subjects with obesity or overweight without T2DM, a study effect cannot be ruled out. However, lower CL/F estimates in normoglycemic subjects with obesity compared to subjects with obesity and T2DM have consistently been reported for other mono or dual GLP1R agonists [3,4]. The post hoc analysis suggested that ADA had no impact on survodutide PK. The remaining covariates were not found to be statistically significant or clinically relevant. IIV on survodutide exposure is expected to be adequately managed by a flexible dose escalation to the maintenance dose.
Conclusions: The population PK of survodutide was best described by first-order kinetics. Among the different covariates that were evaluated, only WT had a relevant effect on the steady state exposure of survodutide, with heavier subjects being less exposed in terms of AUCτ,ss and Cmax,ss compared to lighter subjects. The observed magnitude of the covariate effects alongside the flexible dose escalation scheme suggests that no dose adjustments are warranted for survodutide.
References:
[1] Jungnik et al. Diabetes Obes Metab. 25(4):1011-1023 (2023).
[2] Svensson and Jonsson. CPT:PSP. 2022;11(9):1210-1222.
[3] Overgaard et al. Clin Pharmacokinet. 2016 Nov;55(11):1413-22
[4] http://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000ClinPharmR.pdf
