Mechanism‐based models for topotecan‐induced neutropenia

  title={Mechanism‐based models for topotecan‐induced neutropenia},
  author={Fr{\'e}d{\'e}ric L{\'e}ger and Walter J. Loos and Roland Bugat and Ron H. J. Mathijssen and Marine Goffinet and Jaap Verweij and Alex Sparreboom and Etienne Chatelut},
  journal={Clinical Pharmacology \& Therapeutics},
A semiphysiologic pharmacokinetic‐pharmacodynamic model was applied to describe topotecan‐induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. 
Towards Quantitative Systems Pharmacology Models of Chemotherapy‐Induced Neutropenia
  • M. Craig
  • Medicine
    CPT: pharmacometrics & systems pharmacology
  • 2017
The shift towards quantitative systems pharmacology (QSP) efforts is detailed, emphasizing the importance of incorporating systems‐level physiological considerations in pharmacometrics.
Prediction of Neutropenia‐Related Effects of a New Combination Therapy With the Anticancer Drugs BI 2536 (a Plk1 Inhibitor) and Pemetrexed
This study investigated the feasibility of predicting the neutropenia‐related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo‐like kinase 1) and pemetrexed, an
Mechanism‐based Pharmacokinetic/Pharmacodynamic Meta‐analysis of Trabectedin (ET‐743, Yondelis) Induced Neutropenia
A pharmacokinetic–pharmacodynamic model that describes the time course of the absolute neutrophil counts (ANCs) in cancer patients receiving trabectedin confirmed that neutropenia is reversible, of short duration, and non‐cumulative.
Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development
Simulations showed that all MTD doses showed an acceptable risk of neutropenia, and when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and baseline ANC might be considered to individualise the dose of BI 192536.
A tool for neutrophil guided dose adaptation in chemotherapy
This paper describes the transfer of a previously developed semi-mechanistic model for myelosuppression from NONMEM to a dosing tool in MS Excel, which proved capable to solve a differential equation system describing the pharmacokinetics and pharmacodynamics, with estimation performance comparable to NONM EM.
Semi-mechanistic modelling of neutropenia
  • Elham Alshammari
  • Chemistry
    International Journal of Research in Pharmaceutical Sciences
  • 2019
Population pharmacokinetics and pharmacodynamics PKPD modelling of chemotherapy-induced neutropenia can help with efficacy optimization and toxicity prevention in cancer patients. These medications
Dose Adaptation Based on Pharmacometric Models
Many drugs exhibit major variability in both pharmacokinetic (PK) and pharmacodynamic (PD) parameters that prevents the use of the same dose for all patients. Variability can occur both between pat
Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies
The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents and provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.
Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model
This method for interspecies scaling was successful in predicting the time-course of myelosuppression in patients based on rat data, and appears promising for predicting myelotriment in patients early in development.
Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients
The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted and higher amount of CD34+ cells in the PBSC transplation and earlier administration rHuG-CSF were associated with faster haematological recovery.


Model of chemotherapy-induced myelosuppression with parameter consistency across drugs.
A semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs, is proposed and can be a useful tool in the development of anticancer drugs and therapies.
Pharmacodynamic model of topotecan-induced time course of neutropenia.
A pharmacokinetic-pharmacodynamic model is developed to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutopenia.
Individual adaptive dosing of topotecan in ovarian cancer.
Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60ml/min (recommended starting dose is 1.2 mg/m(2)).
Factors affecting pharmacokinetic variability of oral topotecan: a population analysis
A population pharmacokinetic model has been developed that incorporates measures of renal function and PS to predict CL and in combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan.
Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.
Assessment of the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects concluded that the antitumor efficacy of both schedules should be evaluated in a randomized phase II study.
Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor.
The apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study illustrates significant systemic exposure to the drug which may enable chronic oral treatment.
A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors.
  • V. Santana, W. Zamboni, +5 authors C. Stewart
  • Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2003
Protracted topotecan dosing using a pharmacokinetic strategy was possible in this heavily pretreated group of children with recurrent solid tumors and 78% of the measured AUC values were within the target range.
Phase I and pharmacologic study of topotecan in patients with impaired renal function.
Dose adjustments are required in patients with moderate, but not mild, renal impairment, and the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks.
A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients.
The establishment of a well-tolerated, weekly regimen of topotecan provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.
A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)
No schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored, according to pharmacokinetic/pharmacodynamic relationships from four Phase I studies of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy.