title: Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia.
abstract: This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naive and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half-life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug-related PD parameters or system-specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA-Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.
authors.affiliation: PharmD, Pharsight - A Certara Company, Lyon, France. chanu.pascal@wanadoo.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Chanu
authors.forename: Ronald
authors.initials: R
authors.lastname: Gieschke
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Charoin
authors.forename: Anne
authors.initials: A
authors.lastname: Pannier
authors.forename: Bruno
authors.initials: B
authors.lastname: Reigner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006454:Hemoglobins / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007676:Kidney Failure, Chronic / Q000150:complications; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins; D013997:Time Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols