A tool for neutrophil guided dose adaptation in chemotherapy

Abstract

c o m p u t e r m e t h o d s a n d p r o g r a m s i n b i o m e d i c i n e 9 3 ( 2 0 0 9 ) 283-291 j o u r n a l h o m e p a g e : w w w . i n t l . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c m p b A tool for neutrophil guided dose adaptation in chemotherapyJohan E IntroductionNeutropenia is a major side-effect of many antitumor agents, and is often the dose-limiting factor [1] The risk of infection is related to the degree and duration of neutropenia [2,3]. Dose adjustment to minimize the risk of experiencing severe neutropenia could either be made a priori or a posteriori, ranging in complexity from body size based dosing up to utilization of statistical models and various sampling. In this paper we show implementation of a pharmacokinetic-pharmacodynamic model, describing the neutrophil concentrations after anti-cancer treatment, in a simple tool to be used in the patient care at the clinic. This tool would facilitate use of neutrophil data from the first completed course of treatment in a Bayesian maximum a posteriori process to guide dose selection in an upcoming course. Etoposide was chosen as a model substance, due to it being rather * Corresponding author at: Division of Pharmacokinetics and Drug Therapy, Biomedical Centre, Uppsala University, Sweden. Tel.: +46 18 471 4639; fax: +46 18 471 4003. E-mail address: johan.wallin@farmbio.uu.se (J.E. Wallin).well-characterized and its wide-spread use, and the access to a suitable validation dataset. A predictive model of myelosuppression could be used for dose individualization, in order to avoid neutropenia, a prolonged treatment interval and/or a suboptimal tumor effect. For etoposide current treatment guidelines state that occurrence of severe neutropenia should lead to a reduction or postponement of next dose until neutrophil recovery [4]. The dose reduction is not necessarily tailored to the patient, but usually by fixed decrements such as to 75% or 50% of the original dose. This leads to a one-sided dose adjustment, where only patients experiencing toxicity receives a dose change, but not necessarily in an optimal fashion. The possibility that patients experiencing only a minor myelosuppression are underexposed and might benefit from an increased dose is not taken into account. The relation between hematological toxicity and patient survival has been investigated in clinical 0169-2607/$ -see front matter

Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression

“…No indication of systematic shifts in the systemor drug sensitivity-related parameters over time across data sets was present. Th e time-course of myelosuppression is thereby shown to be predictable within a patient which supports the use of the recently developed model-based dose individualization tool based on observed neutrophil counts [7]. Th is study is thus a valuable step towards individually tailored anticancer drug therapy when myelosuppression is dose-limiting.…”

“…A way to do this could be to use the observed neutrophil counts from one treatment cycle as a base for dose adjustment in the next cycle. A model-based tool for effi cient dose individualization based on neutrophil counts has recently been developed [7]. Th is tool uses a maximum a posteriori (Bayesian) approach to calculate a suitable dose for the next course based on a previously developed population pharmacokinetic-pharmacodynamic model for chemotherapy-induced myelosuppression [8] and observed neutrophil counts.…”

Population Pharmacodynamic Model for Bayesian Prediction of Myelosuppression Profiles Based on Routine Clinical Data after Gemcitabine and Carboplatin Treatment

“…In some cases, such pharmacokinetic information are taken from a phase I clinical study and combined with the myelosuppression data in patients [26] . Wallin et al [27] developed a Bayesian prediction tool of myelosuppression using a population pharmacokinetic/pharmacodynamic model that requires drug concentration data. However, applications of such model analyses to routine clinical chemotherapies are difficult with poor availability of pharmacokinetic data, such as plasma drug concentrations, and more pragmatic models are required.…”

Challenges in cancer research and multifaceted approaches for cancer biomarker quest

“…In spite of all precautionary efforts, frequency of secondary side effects and toxicity remains high. Neutropenia is one common example of a side effect of many anti-cancer agents and is related to an increased risk of infection and mortality [18]. This also reflects the general situation that therapeutic standards are based on average efficacy determined by controlled clinical trials involving large cohort of patients and generally extended to the whole population.…”

“…This technique is based on chemically tagging the N-terminus of peptides generated from protein digests that have been isolated for instance from cells cultured under different experimental conditions or other biological materials [53,54]. A specific way to introduce isotope label into peptide is the use of trypsin-catalysed incorporation of 18 O during protein digestion. The incorporated labels create specific mass tags that can be recognised by mass spectrometry and at the same time provide the basis for quantification.…”