title: Model-based neutrophil-guided dose adaptation in chemotherapy: evaluation of predicted outcome with different types and amounts of information.
abstract: One of the most employed approaches to reduce severe neutropenia following anticancer drug regimens is to reduce the consecutive dose in fixed steps, commonly by 25%. Another approach has been to use pharmacokinetic (PK) sampling to tailor dosing, but only rarely have model-based computer approaches utilizing collected PK and/or pharmacodynamic (PD) data been used. A semi-mechanistic model for myelosuppression that can characterize the interindividual and interoccasion variability in the time-course of neutrophils following administration of a wide range of anticancer drugs may be used in a clinical setting for model-based dose individualization. The aim of this study was to compare current stepwise procedures to model-based dose adaptation by simulations, and investigate if the overall dose intensity in the population could be increased without increasing the risk of severe toxicity. The value of various amounts of PK- and/or PD-information was compared to standard dosing strategies using a maximum a posteriori procedure in NONMEM. The results showed that when information on neutrophil counts was available, the additional improvement from PK sampling was negligible. Using neutrophil sampling at baseline and an observation near the predicted nadir increased the number of patients in the target range by 27% in comparison with a one-sided 25% dose adjustment schedule, while keeping the number of patients experiencing severe toxicity at a comparable low level after five courses of treatment. High interindividual variability did not limit the benefit of model-based dose adaptation, whereas high interoccasion variability was predicted to make any dose adaptation method less successful. This study indicates that for successful model-based dose adaptation clinically, there is no need for drug concentration sampling, and that one extra neutrophil measurement in addition to the pre-treatment value is sufficient to limit severe neutropenia while increasing dose intensity.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Johan E
authors.initials: JE
authors.lastname: Wallin
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D006801:Humans; D007958:Leukocyte Count; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D057285:Precision Medicine