title: Semimechanistic cell-cycle type-based pharmacokinetic/pharmacodynamic model of chemotherapy-induced neutropenic effects of diflomotecan under different dosing schedules.
abstract: The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.
authors.affiliation: Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.).
authors.forename: Víctor
authors.identifier: http://orcid.org/0000-0002-2503-3373
authors.initials: V
authors.lastname: Mangas-Sanjuan
authors.affiliation: Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.).
authors.forename: Núria
authors.initials: N
authors.lastname: Buil-Bruna
authors.affiliation: Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.).
authors.forename: María J
authors.initials: MJ
authors.lastname: Garrido
authors.affiliation: Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.).
authors.forename: Elena
authors.initials: E
authors.lastname: Soto
authors.affiliation: Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.) itroconiz@unav.es.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle; D049109:Cell Proliferation; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C424962:diflomotecan; D002166:Camptothecin