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Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke.

Abstract：

BACKGROUND AND OBJECTIVES: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. METHODS: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. PATIENTS: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). MAIN OUTCOME MEASURES AND RESULTS: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. CONCLUSION: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.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Jönsson S,Cheng YF,Edenius C,Lees KR,Odergren T,Karlsson MO

doi

10.2165/00003088-200544080-00007

keywords:

subject

Has Abstract

pub_date

2005-01-01 00:00:00

pages

863-78

issue

eissn

0312-5963

issn

1179-1926

pii

4487

journal_volume

pub_type

杂志文章,多中心研究,随机对照试验

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Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke.