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Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2005 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 44, no 8, 863-878 p.Article in journal (Refereed) Published
Abstract [en]


NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.


NXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CL(CR)). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CL(CR) or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfillment criteria and parsimony.


Pharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34-92 years with varying degrees of renal impairment (estimated CL(CR) 20-143 mL/min).


The final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CL(CR) and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CL(CR) of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CL(CR) (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.


The results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

Place, publisher, year, edition, pages
2005. Vol. 44, no 8, 863-878 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91733PubMedID: 16029070OAI: oai:DiVA.org:uu-91733DiVA: diva2:164562
Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2011-10-07Bibliographically 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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