Population pharmacokinetic analysis of axitinib in healthy volunteers

AIMS

Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers.

METHODS

Plasma concentration–time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19).

RESULTS

A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (V_c), absorption rate constant (k_a) and absolute bioavailability (F) were 17.0 l h⁻¹, 45.3 l, 0.523 h⁻¹ and 46.5%, respectively. With axitinib Form IV, k_a and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected V_c, but the effect was within the estimated interindividual variability for V_c.

CONCLUSIONS

The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. V_c was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.     

Increased atherosclerosis in mice with increased vascular biglycan content

Objective

The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development.

Methods

Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4–12 weeks.

Results

LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content.

Conclusion

Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development.