title: Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies.
abstract: In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain. msoto@alumni.unav.es
authors.forename: Elena
authors.initials: E
authors.lastname: Soto
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Josep María
authors.initials: JM
authors.lastname: Cendrós
authors.forename: Rosendo
authors.initials: R
authors.lastname: Obach
authors.forename: Concepción
authors.initials: C
authors.lastname: Peraire
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D011237:Predictive Value of Tests; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; C424962:diflomotecan; D002166:Camptothecin
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