A Population Pharmacokinetic–Pharmacodynamic Model for Simvastatin that Predicts Low‐Density Lipoprotein‐Cholesterol Reduction in Patients with Primary Hyperlipidaemia

Abstract

Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and sim-vastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data. Simvastatin (SV) is a HMG-CoA reductase inhibitor effective in the treatment of hypercholesterolaemia and hypertri-glyceridaemia [1]. It is widely used to reduce the risk of cardiovascular morbidity and mortality [2] and thromboem-bolic stroke in high-risk patients [3,4]. After oral administration , simvastatin is rapidly absorbed (t max of 1-2 hr) [5,6] and eliminated. Less than 10% of the peak HMG-CoA reductase inhibitory activity remains after 12 hr (t 1 ⁄ 2 = 2-5 hr) [5,7]. Once administered, simvastatin rapidly undergoes reversible non-enzymatic or carboxylesterase-mediated conversion to its active metabolite, simvastatin acid (SVA), in the liver, intestinal mucosa and plasma [1,8]. CYP450 is also known to metabolize a small fraction of simvastatin. Simvastatin acid prevents HMG-CoA reductase from converting HMG-CoA to mevalonate, which is a rate-limiting step in cholesterol biosynthesis [9]. Inhibition of the HMG-CoA reductase in the liver results in the reduction in cholesterol synthesis. Moreover, the up-regulation of low-density lipoprotein (LDL) receptors located on the cell membranes of the liver and extrahepatic tissues thereby also contributes to the reduction in plasma LDL-cholesterol (LDL-C) concentrations [10]. There are many reports on the safety, efficacy and metabolism of simvastatin. To date, there have been no published population pharmacokinetic-pharmacodynamic (PK-PD) models for simvastatin or simvastatin acid. Recently, we performed a drug-drug interaction s...

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

“…We identified two population PKPD models for simvastatin [10,11,17] and one population pharmacokinetic (PK) …”

“…Table 1 summarizes the population parameter estimates, structural components and error models used for all simulations. These were derived directly from the published model [10,17].…”

“…The parameters A, x and F were taken from a published study defining the per cent change in the fractional synthetic rate of cholesterol, as measured using deuterium-enriched plasma cholesterol [19]. The parameter M was the population estimate of LDL synthetic rate in mg ⁄ dL ⁄ hr from the published PKPD model [10,17].…”

“…The full details of model development have been published elsewhere [10,17]. In brief, the model was developed using data collected from 27 healthy male volunteers who were given 40 mg of simvastatin at 9.00 a.m. daily for 14 days.…”

“…We identified two population PKPD models for simvastatin [10,11,17] model [18]. Of these, only the model produced by Kim et al [10,17] provided sufficient information (e.g.…”