Qianwen Wang1, Mr Ahmed Nader2, Ms Shuying Yang1
1Clinical Pharmacology Modelling and Simulation, GSK,, 2Clinical Pharmacology Modelling and Simulation, GSK
Objectives: Ibrexafungerp is a triterpenoid antifungal agent that is under development for the treatment of adults with invasive Candida infections (ICI), including candidemia [1, 2]. During development of ibrexafungerp, multiple routes (intravenous [IV] and oral) and formulations as well as food effect were investigated. The aims of this analysis were to develop a comprehensive population pharmacokinetic (popPK) model of ibrexafungerp to describe the pharmacokinetics (PK) of ibrexafungerp and to quantify the influence of covariates. Methods: Data from 12 Phase 1 studies where intensive PK data following IV and oral administration in healthy volunteers (HV) were used. A base structural model was selected based on the intensive PK data from IV administration. PK data from oral administration was subsequently incorporated into the model. One or multi-compartment models with first-order elimination were considered. Different absorption models were considered, e.g. first-order absorption with or without lag-time, and more complex transit models. The first-order conditional estimation method with interaction (FOCE-I) was used for parameter estimation. Covariates including demographic variables, formulations (including capsule, phosphate tablet, citrate tablet, or lipid dispersion tablet), food effect (fasted, low-fat diet or high-fat diet) were assessed. Stepwise covariate model (SCM) was used to select the statistically significant and scientifically plausible covariates. Model performance was evaluated using goodness-of-fit plots and visual predictive checks. Results: A total of 6699 observations from HV were included in the popPK model (n=1350 from IV, n=5349 from oral). A two-compartment model with first-order elimination characterised the PK profile following IV administration. Structural PK parameters were fixed: intrinsic clearance (CL) of 16.6 L/h, central volume of distribution (V2) of 19.8 L, intercompartmental clearance (Q) of 75.9 L/h, and peripheral volume of distribution (V3) of 348 L when oral data was included, and the absorption model was added. A transit model best described the absorption phase of ibrexafungerp after oral administration. The estimated mean transit time (MTT) was 0.133 h, and absolute bioavailability (F1) was 0.256. Covariate analysis revealed that formulation and food effect were significant covariates on F1 and MTT. The final formulation to be used in clinical setting is citrate tablet. Model estimated mean (10–90th percentile) of F1 for participants taking citrate table at fasted, with low-fat diet or with high-fat diet were 0.19 (0.12–0.33), 0.59 (034–0.88), 0.29 (0.21–0.53), respectively. Model estimated mean (10–90th percentile) of MTT for participants taking citrate table at fasted, with low-fat diet or with high-fat diet were 0.19 (0.14–0.24) hr, 0.07 (0.05–0.14) hr and 0.16 (0.12–0.21) hr. The underlying mechanisms driving the complex impact of covariates on F1 and MTT will be further investigated. Sex was also identified as a significant covariate on MTT, with female subjects having 21.1% longer MTT. Additionally, Q was associated with age and weight whereas V3 was associated with weight. For 10 kg weight increase, Q and V3 were increased by 10%. For 10 years increase in age, V3 decreased approximately 7%. PK data from 5 studies where sparse PK were collected in patients following oral administration will be added to the model as a next step, to understand the impact of disease population on exposure of ibrexafungerp. The effect of the identified covariates will also be further assessed. Conclusions: The observed PK of ibrexafungerp in HV was well described by the final popPK model. The impact of covariates on ibrexafungerp was quantified, among which formulation and food effect were significant covariates on both rate and extent of absorption after oral administration of ibrexafungerp. Impact of disease population on exposure will be evaluated as a next step. A final comprehensive model will be used to further investigate the relationship between exposure and relevant efficacy or safety endpoints.
[1] Jallow S, Govender NP. Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor. J Fungi (Basel). 2021 Feb 25;7(3):163. doi: 10.3390/jof7030163. PMID: 33668824; PMCID: PMC7996284. [2] Allaw, Fatima, Elie Moussa, and Souha S. Kanj. “Ibrexafungerp: A narrative overview.” Current Research in Microbial Sciences (2024): 100245.
Reference: PAGE 33 (2025) Abstr 11739 [www.page-meeting.org/?abstract=11739]
Poster: Drug/Disease Modelling - Infection