title: Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Sanofi, 371 rue du Pr. J. Blayac, 34184, Montpellier Cedex 04, France. nassim.djebli@sanofi.com.
authors.forename: Nassim
authors.initials: N
authors.lastname: Djebli
authors.affiliation: Sanofi, 371 rue du Pr. J. Blayac, 34184, Montpellier Cedex 04, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Martinez
authors.affiliation: Université de Montpellier, UFR Pharmacie, Pharmacocinétique, Montpellier, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Lohan
authors.affiliation: Université de Montpellier, UFR Pharmacie, Pharmacocinétique, Montpellier, France.|Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Khier
authors.affiliation: Sanofi, 371 rue du Pr. J. Blayac, 34184, Montpellier Cedex 04, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Brunet
authors.affiliation: Sanofi, 371 rue du Pr. J. Blayac, 34184, Montpellier Cedex 04, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Hurbin
authors.affiliation: Sanofi, 371 rue du Pr. J. Blayac, 34184, Montpellier Cedex 04, France.
authors.forename: David
authors.initials: D
authors.lastname: Fabre
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D064368:Healthy Volunteers; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D008954:Models, Biological; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000097:blood*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C571059:alirocumab
keywords: Familial Hypercholesterolemia; Linear Clearance; Objective Function Value; PopPK Model; Visual Predictive Check