uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Model-Based Neutrophil-Guided Dose Adaptation in Chemotherapy: Evaluation of Predicted Outcome with Different Types and Amounts of Information
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri, Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri, Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri, Pharmacometrics)
2010 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 3, 234-242 p.Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 106, no 3, 234-242 p.
National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-100496DOI: 10.1111/j.1742-7843.2009.00520.xISI: 000274454300014PubMedID: 20050841OAI: oai:DiVA.org:uu-100496DiVA: diva2:210450
Available from: 2009-04-01 Created: 2009-04-01 Last updated: 2011-01-04Bibliographically approved
In thesis
1. Dose Adaptation Based on Pharmacometric Models
Open this publication in new window or tab >>Dose Adaptation Based on Pharmacometric Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
Model Based Dose Adaptation
Abstract [en]

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 patients (IIV) as well as within patients over the course of time (IOV). In a drug with narrow therapeutic range and substantial IIV, dose selection may require individual adaptation. Adaptation can either be made before (a priori) or after (a posteriori) first drug administration. The former implies basing the dose on prior information known to be influential, such as kidney function indicators, weight or concomitant medication, whereas a posteriori dose adaptations are based on post-treatment observations. Often individualization cannot be based on the clinical outcome itself. In such cases, drug concentrations or biomarkers may be valuable for dose individualisation.

In this thesis two therapeutic areas where dosing is critical have been investigated regarding the possibilities of a priori and a posteriori dose adaptation; anticancer treatment where myelosuppression is dose limiting, and tacrolimus used for immunosuppression in paediatric transplantation. In tacrolimus previously published models were found to be of little value for dose adaptation in the early critical days post-transplantation. New PK models were developed and used to suggest new dosing regimens tailored for the paediatric population, recognizing the changing pharmacokinetics in the early time post-transplantation.

For several anticancer drugs covariates were identified that partly explained IIV in myelosuppression. IOV were found to be lower than IIV which implies that individual dose adaptations a posteriori can be valuable. Dose adaptation, using Bayesian principles in order to simultaneously minimise the risk of severe toxicity or subtherapeutic levels, was evaluated using simulations. Type and amount of data needed, as well as variability parameters influential on the outcome, were evaluated. Results show drug concentrations being of little value, if neutrophil counts are available.

The models discussed in this thesis have been implemented in MS Excel macros for Bayesian forecasting, to allow widespread distribution to clinical settings without necessitating access to specific statistical software.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 94
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100569 (URN)978-91-554-7488-1 (ISBN)
Public defence
2009-05-15, B41, BMC, Dag Hammarsköldsväg, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-02 Last updated: 2011-05-11Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Wallin, Johan E.Friberg, Lena E.Karlsson, Mats O.

Search in DiVA

By author/editor
Wallin, Johan E.Friberg, Lena E.Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Basic & Clinical Pharmacology & Toxicology
Pharmacology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 479 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf