The Influence of Dosing Time, Variable Compliance and Circadian Low-Density Lipoprotein Production on the Effect of Simvastatin: Simulations from a Pharmacokinetic-Pharmacodynamic Model

Abstract

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.Elevated plasma low-density-lipoprotein (LDL) concentrations have been linked to an increased risk of cardiovascular and cerebrovascular morbidity and mortality [1,2]. It has been proposed that a reduction in plasma LDL by 1 mmol ⁄ L will result in about a 20% reduction in adverse vascular events, regardless of the baseline concentration [3]. This would represent a 25-35% reduction in LDL concentration from a baseline of 3-4 mmol ⁄ L. Simvastatin reduces serum LDL concentrations by inhibiting HMG-CoA reductase, the rate-limiting enzyme for cholesterol production in the liver.Cholesterol synthesis follows a circadian pattern, with peak production occurring between midnight and 6.00 a.m. [4,5]. It is usually recommended that daily doses of simvastatin be taken in the evening on the grounds that this will allow peak simvastatin concentrations to occur at the same time as peak circadian cholesterol production [6][7][8][9]. Hence, it is generally assumed that evening dosing will result in a greater reduction in plasma LDL compared with morning dosing. However, the rate-limiting step in the time course of simvastatin effect on cholesterol is not the half-life of simvastatin but the relatively slow turnover of cholesterol itself. The estimated half-life of cholesterol in the plasma is in the order of 3-4 days [9]. As a result, the peak effect of simvastatin on LDL reduction has been found to be substantially delayed with respect to the peak plasma concentration of the drug [10,11]. This suggests that dosing simvastatin in the evening and measuring LDL in the morning may not necessarily reflect the greatest effect on plasma cholesterol concentrations.Compliance with evening dosing has been found to be 5-25% lower compared with morning dosing for a variety of cardiovascular dru...

Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach

“…Atherosclerosis and the effect of statins in humans have been analyzed in the past using conventional pharmacokinetics and pharmacodynamics (PKPD) modeling approaches (Kim et al, 2011 ; Wright et al, 2011 ). In particular, Wright et al ( 2011 ) explored the influence of variable compliance, circadian cholesterol production and simvastatin dosing time on the reduction of low-density lipoprotein (LDL).…”

“…Atherosclerosis and the effect of statins in humans have been analyzed in the past using conventional pharmacokinetics and pharmacodynamics (PKPD) modeling approaches (Kim et al, 2011 ; Wright et al, 2011 ). In particular, Wright et al ( 2011 ) explored the influence of variable compliance, circadian cholesterol production and simvastatin dosing time on the reduction of low-density lipoprotein (LDL). This work mainly showed the impact of medication adherence on the effect of statins on decreasing LDL levels in blood, however, to our knowledge there are no previous attempts where a multiscale approach as the one proposed here has been used to include models of downstream biology/physiology in order to study the effect of these drugs on the disease development and progression (i.e., atherosclerosis).…”

Using a Systems Pharmacology Approach to Study the Effect of Statins on the Early Stage of Atherosclerosis in Humans

“…The main advantage of this approach is that each individual module can be improved (for example, by adding more mechanisms based on new evidence or data) or simplified being the ultimate goal the validation of all the biological/physiological scales considered in this type of model. More specifically, future changes in the PKPD module to improve the whole model might consider: Modeling the effect of circadian rhythms on the LDL levels as proposed by Wright et al The inclusion of the pleiotropic effect of statins, using a similar approach to that proposed by Rose et al .…”

“…1. Modeling the effect of circadian rhythms on the LDL levels as proposed by Wright et al 37 2. The inclusion of the pleiotropic effect of statins, using a similar approach to that proposed by Rose et al 38 (modifying the PK model proposed here)…”

From PK/PD to QSP: Understanding the Dynamic Effect of Cholesterol-Lowering Drugs on Atherosclerosis Progression and Stratified Medicine

“…[20] (Fig. 4 ) explored the influence of simvastatin dosing time, variable compliance and circadian cholesterol production on the reduction of low-density lipoprotein (LDL).…”