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Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies.

Abstract：

BACKGROUND AND OBJECTIVE:Proprotein convertase subtilisin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering therapies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in healthy subjects and patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS:This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subsequently expanded to a larger data set of 13 studies (n = 2870). Potential model parameters and covariate relationships were explored, and predictive ability was qualified using a visual predictive check. RESULTS:The TMDD model was built using the quasi-steady-state approximation. The final TMDD-quasi-steady-state model included a significant relationship between distribution volume of the central compartment and disease state: distribution volume of the central compartment was 1.56-fold higher in patients vs. healthy subjects. Separately, application of the model to the expanded data set revealed a significant relationship between linear clearance and statin co-administration: linear clearance was 1.27-fold higher with statins. The good predictive performance of the TMDD model was assessed based on graphical and numerical quality criteria, together with the visual predictive check and comparison of the predictions to those from a PopPK model with parallel linear and Michaelis-Menten clearances (i.e., simplification of the TMDD PopPK model). CONCLUSIONS:This mechanistic TMDD PopPK model integrates the interaction of alirocumab with its target and accurately predicts both alirocumab and total proprotein convertase subtilisin/kexin type 9 concentrations in healthy subjects and patients.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Djebli N,Martinez JM,Lohan L,Khier S,Brunet A,Hurbin F,Fabre D

doi

10.1007/s40262-016-0505-1

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

1155-1171

issue

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-016-0505-1

journal_volume

pub_type

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Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies.