V. Piotrovskij, V. Van de Velde, A. Van Pee
Janssen Research Foundation, International Clinical R & D, Clinical Pharmacokinetics, 2340 Beerse, Belgium
Lubeluzole is a benzotriazole derivative exhibiting anti-hypoxic properties which is currently being developed for the use in ischaemic stroke. Population analysis of its pharmacokinetics was performed using the NONMEM software. Plasma concentration data were from 15 clinical trials in which the drug was infused intravenously. There were 13 phase I/II studies in healthy volunteers or ischaemic stroke patients with frequent plasma sampling, and 3 efficacy trials with sparse sampling. In total, there were 5756 plasma concentration measurements from 876 subjects. A two-compartment structural model parameterized in terms of the total clearance (CL), central (Vc) and peripheral (Vp) volumes of distribution, and distributional flow (Q) was selected. A regression model for fixed effects was built in a standard way which included fitting a population model containing only random effects and subsequent analysis of relationships between Bayesian estimates of individual parameters and covariates using S+ software. Covariates that exhibited significant effects were included into the NONMEM model. A correlation between parameters was also evaluated. The significance of fixed and random effects was then tested by backward elimination of parameters using a chi-square test.
Lubeluzole CL was found to decrease with age (0.032 L/h per year) and increase with LBM (0.07 L/h per kg). A basal typical value of CL was 7.1 L/h in 70 yr. old and 55 kg LBM stroke patient. LBM was found to be better predictor of CL as compared with WT or BSA. In case of liver of kidney dysfunction CL was about 30 % less. The gender effect on CL was related to differences in LBM between males and females. There was no specific difference in CL between healthy volunteers and stroke patients, and no specific effects of race or the country of the study, and the total dose infused. In smokers, CL did tend to be higher than in nonsmokers. Vc was 61 L (independent on any body size parameters or other demographic covariates) and was lower in renal or hepatic insufficiency. Vss was proportional to WT and was significantly lower in male subjects (2.5 L/kg) as compared to females (3.4 L/kg) which is related to the gender difference in fat contents in the body. Q was 30L/h (500 mL/min), and no effects of any covariates on it were detected. The median T1/2 was equal to 20 and 28.7 h, respectively. There was a covariance between CL and Vc, and between Vp and Q.
Reference: PAGE 6 () Abstr 663 [www.page-meeting.org/?abstract=663]
Poster: poster