Clinical pharmacokinetics · 2025
Population Pharmacokinetics and Pharmacodynamics Modeling for the Use of Recaticimab in Healthy Volunteers and Patients with Hypercholesterolemia.
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Shu Chang, Wang Ying, Feng Sheng, Yang Shengxian, Shen Kai
Аннотация
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C from circulation. By inhibiting PCSK9, it is possible to provide early intervention to achieve clinical benefits.
METHODS: The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model.
RESULTS: A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates.
DISCUSSION: No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy.
TRIAL REGISTRATION: NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.
METHODS: The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model.
RESULTS: A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates.
DISCUSSION: No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy.
TRIAL REGISTRATION: NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.