title: Dose schedule optimization and the pharmacokinetic driver of neutropenia.
abstract: Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Mayankbhai
authors.initials: M
authors.lastname: Patel
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Palani
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Arijit
authors.initials: A
authors.lastname: Chakravarty
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Johnny
authors.initials: J
authors.lastname: Yang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Wen Chyi
authors.initials: WC
authors.lastname: Shyu
authors.affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Jerome T
authors.initials: JT
authors.lastname: Mettetal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008954:Models, Biological; D008962:Models, Theoretical; D009503:Neutropenia / Q000139:chemically induced*; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D005047:Etoposide; D019772:Topotecan