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


METHODS
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).


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.


CONCLUSIONS
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.
Jönsson
Siv
S
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden.
Cheng
Yi-Fang
YF
Edenius
Charlotte
C
Lees
Kennedy R
KR
Odergren
Tomas
T
Karlsson
Mats O
MO
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001557:Benzenesulfonates; D003404:Creatinine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics*; D009589:Nitrogen Oxides / Q000097:blood / Q000493:pharmacokinetics*; D020521:Stroke / Q000517:prevention & control*
D001557:Benzenesulfonates; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium; D003404:Creatinine