The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.

The aim of this study was to explore the influence of simvastatin dosing time, variable compliance and circadian cholesterol production on the reduction of low-density lipoprotein (LDL). A published pharmacokinetic-pharmacodynamic (PKPD) model for simvastatin was identified and evaluated. A model for circadian LDL production was incorporated into the PKPD model. Reduction in LDL from baseline was simulated stochastically from the full model at dose levels of 10, 20, 40 and 80 mg daily for 30 days. Simulated dosing times for each data set were morning (8.00 a.m.), evening (22.00 p.m.), evening with reduced compliance and evening for a hypothetical bioequivalent generic. Differences in LDL reduction from baseline between evening (33-43%) and morning dosing (31-43%) were negligible across a range of doses. Any differences were negated when variable compliance was considered. In addition, differences in simvastatin effect between morning and evening dosing were found to be within the range of LDL concentrations that would be permissible for a bioequivalent generic (at the lower limit) and hence are not likely to be important clinically. The results of this study suggest that taking simvastatin in the evening is not superior to morning dosing.