(T-061) A semi-mechanistic PKPD model of CSL112 harmonizes the differential cholesterol efflux capacities (CEC) of high-density lipoprotein across different dose groups

Xiaoxi Liu – CSL Behring; Silpa Nuthalapati – CSL Behring; Bernardo De Miguel Lillo – CSL Behring; Milin Acharya – CSL Behring; Partha Nandy – CSL Behring

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Objectives: CSL112 is a novel intravenous (IV) formulation of apoA-1 purified from human plasma and was developed to reduce the risk of major adverse cardiovascular events in acute myocardial infarction (AMI) patients. The central premise of CSL112 is based on apoA-I’s ability to increase CEC of serum and to remove cholesterol from plaques. In a Phase 2 study (CSLCT-HDL-12-77), CSL112 exhibited different trends of CEC dynamics between low and high dose groups. We aimed to develop a model that harmonizes the observed PD behaviors.

Methods: Data from seven previous clinical studies (four Phase 1 studies and three Phase 2 studies, including CSLCT-HDL-12-77) was used to develop the popPK and popPKPD model. The popPK model was previously published and remained the same. The PD model was previously a simple Emax model, and now updated with a semi-mechanistic PD structure that reflects HDL’s remaining capacity of cholesterol uptake, which hypothetically diminishes over time as it collects cholesterol from plaques. All models were developed with NONMEM7 and postprocessed with Rscript 4.3.2.

Results: With the updated PD structure, the model was able to well characterize the CEC dynamics in both low and high dose groups from study CSLCT-HDL-12-77. Compared with previous model, OFV was reduced by 2533 points and significant improvement of model fitting was achieved. While dose was not introduced as a covariate, the model was still capable of describing the observed CEC behaviors between low and high dose groups.

Conclusions: The current popPKPD model reflects the central mechanism of apoA-I’s ability to increase CEC in serum and the hypothetical dynamics of CEC over time. The model harmonizes the observed ‘dose effect’ between low and high dose groups, without introducing dose as a covariate.

Citations: Zheng B, Duffy D, Tricoci P, et al. Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients. Br J Clin Pharmacol. 2021;87(6):2558-2571. doi:10.1111/bcp.14666

Keywords: PKPD modeling, dose effect, MACE, cholesterol efflux