Back to Search
Start Over
Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke
Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke
- Source :
- Clinical pharmacokinetics. 44(8)
- Publication Year :
- 2005
-
Abstract
- 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.
- Subjects :
- Adult
Male
Metabolic Clearance Rate
Population
Renal function
Models, Biological
Pharmacokinetics
Double-Blind Method
Medicine
Humans
Pharmacology (medical)
Dosing
education
Stroke
Aged
Pharmacology
Volume of distribution
Aged, 80 and over
education.field_of_study
business.industry
Benzenesulfonates
Middle Aged
medicine.disease
NONMEM
Neuroprotective Agents
Pharmacodynamics
Anesthesia
Creatinine
Female
Nitrogen Oxides
business
Subjects
Details
- ISSN :
- 03125963
- Volume :
- 44
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Clinical pharmacokinetics
- Accession number :
- edsair.doi.dedup.....0e94e94b55f6813d1dfbd44721aa550c