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Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2005 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, 123-132 p.Article in journal (Refereed) Published
Abstract [en]

Methods for optimizing dosing strategies for individualization with a limited number of discrete doses, in terms of maximizing the expected utility of treatment or responder probability, are presented. The optimality criteria require models for both beneficial and adverse effects that are part of the utility definition and published population models describing those effects for oxybutynin (urge urinary incontinence episodes per week and severity of dry mouth, respectively) were used for illustration. Dosing strategies with two dosing categories were defined in terms of sizes of the daily doses (low and high dose) and the proportion of patients that can be expected to be preferentially treated at the low dose level. Utility and responder definitions were varied to investigate the influence on the resulting dosing strategy. By minimizing a risk function, describing the seriousness of deviations from the predefined target, optimal dosing strategies were estimated using mixture models in NONMEM. The estimated dose ranges for oxybutynin were similar to those recommended. The optimal individualization conditions were dependent on the definitions of responder and utility. The predicted gain of individualization given utility and responder definitions used was greater, when a responder criteria was maximized compared with maximizing utility.

Place, publisher, year, edition, pages
2005. Vol. 25, no 1, 123-132 p.
Keyword [en]
Dosing strategy, Individualization, Utility and responder definition, Optimization, Risk–benefit, NONMEM
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91735DOI: 10.1016/j.ejps.2005.02.004PubMedID: 15854808OAI: oai:DiVA.org:uu-91735DiVA: diva2:164564
Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2011-10-06Bibliographically approved
In thesis
1. Estimation of Dosing Strategies for Individualisation
Open this publication in new window or tab >>Estimation of Dosing Strategies for Individualisation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

To increase the proportion of patients with successful drug treatment, dose individualisation on the basis of one or several patient characteristics, a priori individualisation, and/or on the basis of feedback observations from the patient following an initial dose, a posteriori individualisation, is an option. Efficient tools in optimising individualised dosing strategies are population models describing pharmacokinetics (PK) and the relation between pharmacokinetics and pharmacodynamics (PK/PD).

Methods for estimating optimal dosing strategies, with a discrete number of doses, for dose individualisation a priori and a posteriori were developed and explored using simulated data. The methods required definitions of (i) the therapeutic target, i.e. the value of the target variable and a risk function quantifying the seriousness of deviation from the target, (ii) a population PK/PD model relating dose input to the target variable in the patients to be treated, and (iii) distributions of relevant patient factors. Optimal dosing strategies, in terms of dose sizes and individualisation conditions, were estimated by minimising the overall risk. Factors influencing the optimal dosing strategies were identified. Consideration of those will have implications for study design, data collection, population model development and target definition.

A dosing strategy for a priori individualisation was estimated for NXY-059, a drug under development. Applying the estimated dosing strategy in a clinical study resulted in reasonable agreement between observed and expected outcome, supporting the developed methodology.

Estimation of a dosing strategy for a posteriori individualisation for oxybutynin, a drug marketed for the treatment of overactive bladder, illustrated the implementation of the method when defining the therapeutic target in terms of utility and responder probability, that is, as a combination of the desired and adverse effects.

The proposed approach provides an estimate of the maximal benefit expected from individualisation and, if individualisation is considered clinically superior, the optimal conditions for individualisation. The main application for the methods is in drug development where the methods can be generally employed in the establishment of dosing strategies for individualisation with relevant extensions regarding population model complexity and individualisation conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 62 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 312
Pharmaceutical biosciences, Dosing strategy, Individualisation, Pharmacokinetic, Pharmacodynamic, Modeling, NONMEM, Decision making, Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-4255 (URN)91-554-5960-9 (ISBN)
Public defence
2004-05-19, Room B21, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2004-04-26 Created: 2004-04-26Bibliographically approved

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