title: Population pharmacokinetic model of lithium and drug compliance assessment.
abstract: Population pharmacokinetic analysis of lithium during therapeutic drug monitoring and drug compliance assessment was performed in 54 patients and 246 plasma concentrations levels were included in this study. Patients received several treatment cycles (1-9) and one plasma concentration measurement for each patient was obtained always before starting next cycle (pre-dose) at steady state. Data were analysed using the population approach with NONMEM version 7.2. Lithium measurements were described using a two-compartment model (CL/F=0.41Lh-1, V1/F=15.3L, Q/F=0.61Lh-1, and V2/F = 15.8L) and the most significant covariate on lithium CL was found to be creatinine clearance (reference model). Lithium compliance was analysed using inter-occasion variability or Markovian features (previous lithium measurement as ordered categorical covariate) on bioavailability parameter. Markov-type model predicted the lithium compliance in the next cycle with higher success rate (79.8%) compared to IOV model (65.2%) and reference model (43.2%). This model becomes an efficient tool, not only being able to adequately describe the observed outcome, but also to predict the individual drug compliance in the next cycle. Therefore, Bipolar disorder patients can be classified regarding their probability to become extensive or poor compliers in the next cycle and then, individual probabilities lower than 0.5 highlight the need of intensive monitoring, as well as other pharmaceutical care measurements that might be applied to enhance drug compliance for a better and safer lithium treatment.
authors.affiliation: Program of Molecular and Cellular Biology, Department of Engineering, University Miguel Hernández de Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550 Alicante, Spain; Department of Clinical Pharmacy, Hospital of Francesc de Borja, Av/ de la Medicina 6, Gandia, 46702 Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Castelló
authors.affiliation: Program of Molecular and Cellular Biology, Department of Engineering, University Miguel Hernández de Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550 Alicante, Spain; Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31008 Pamplona, Navarra, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Mangas-Sanjuan
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Av/ Vicent Andres Estelles, s/n. 46100, Burjasot, 46100 Valencia, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: González-García
authors.affiliation: Program of Molecular and Cellular Biology, Department of Engineering, University Miguel Hernández de Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550 Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonzalez-Alvarez
authors.affiliation: Program of Molecular and Cellular Biology, Department of Engineering, University Miguel Hernández de Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550 Alicante, Spain.
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
authors.affiliation: Department of Clinical Pharmacy, Hospital of Francesc de Borja, Av/ de la Medicina 6, Gandia, 46702 Valencia, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Marco-Garbayo
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31008 Pamplona, Navarra, Spain. Electronic address: itroconiz@unav.es.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008094:Lithium / Q000097:blood; D018020:Lithium Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D015233:Models, Statistical; D010349:Patient Compliance; D011153:Population; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D008094:Lithium
keywords: Drug compliance; Lithium; Markov modelling; Population pharmacokinetic analysis; TDM