The use of PKPD simulations to inform the rational use of medicines in clinical practice: the case of simvastatin circadian dosing

Background: The overarching motivation for this research is the belief that simulations from a pharmacokinetic-pharmacodynamic (PKPD) model provide an opportunity to explore the rational use of medicines in clinical practice. The current practice of dosing simvastatin in the evening rather than the morning is presented as a motivating example. This regimen is based largely on the assumption that, due to its short plasma half-life, simvastatin must be dosed in the evening so that peak plasma concentrations will match peak circadian cholesterol production. However, given the delayed effect of simvastatin on cholesterol production and the reduced compliance with evening dosing, we question the rationale for this practice.

Aims: The aim of this project was to explore the influence of simvastatin dosing time, variable compliance and circadian cholesterol production on the reduction of low-density lipoproteins (LDLs) using simulations from a simvastatin PKPD model.

Methods: A simvastatin PKPD model [1], including a model for the circadian production of cholesterol, was coded into MATLAB (2010b). The model was evaluated against published LDL values from clinical trials. LDL datasets were simulated for 1000 individuals taking simvastatin 5, 10, 20, 40 and 80 mg daily for 30 days. The percent reduction in LDL concentrations from baseline was determined for each dose level after morning dosing, evening dosing and evening dosing with a reduced rate of compliance. A comparison was also made with a hypothetical generic of simvastatin which met the criteria (at the lower extreme) for clinical bioequivalence.

Results: Evening dosing resulted in a slightly greater reduction in LDL from baseline (26-42% reduction) than morning dosing (23-41% reduction) across a range of doses. Absolute differences in LDL reduction between dosing times were found to be dose-dependent, ranging from 3.5% (5mg) to 1% (80mg). Reduction in compliance with evening dosing has been reported to be up to 5-25% greater than morning dosing [e.g 2-4]. The differences between morning and evening dosing were negated when reduced compliance with evening administration was taken into account. Differences in simvastatin effect between morning and evening dosing were also found to be within the range of LDL concentrations permissible for a hypothetical bioequivalent generic simvastatin and hence are not important clinically.

Conclusions: Our simulations suggest that taking simvastatin in the evening is not superior to the morning dosing. PKPD simulations provide a useful means of exploring the rational use of medicines, though the impact on clinical practice has yet to be explored.


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