A novel direct method to determine adherence to simvastatin therapy in patients with coronary heart disease

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): National Association of Health OnBehalf NORCOR Background Poor adherence to statin therapy remains a public health concern associated with adverse clinical outcome. Reliable classification and detection of statin adherence is needed in clinical practice and for clinical studies with overall aim to improve the lipid management. Simvastatin is a frequently used statin in cardiovascular disease prevention. Purpose To develop a feasible test based on spot blood samples to monitor the adherence to simvastatin therapy in coronary heart disease (CHD) patients. Methods Eighteen CHD patients on an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5) and 80 mg (n = 6) were studied at steady-state pharmacokinetics. Ten patients were instructed to avoid simvastatin dosing and return for blood sampling the subsequent three days. Dose-normalized plasma concentrations of simvastatin lactone, simvastatin acid and the sum of the two were evaluated as discriminators between adherent dosing and dose avoidance. Bioanalytical quantifications were performed with liquid chromatography tandem mass spectrometry. Results The dose-normalized plasma concentrations at steady-state demonstrated 23-fold and 39-fold interindividual variabilities for simvastatin lactone and simvastatin acid. A simvastatin acid cut-off at 1.0·10^-2 nmol/L/mg identified 100% of those omitting 2 doses and 60% of those omitting a single dose (Figure 1). Simvastatin acid showed superior ability to discriminate dose avoidance from adherence, and also the best agreement between samples handled at ambient and cool temperature (median deviation 3.5%, interquartile range -2.5 to 13%). A cut-off for morning dose schedule, with similar ability to discriminate, was estimated at 2.0·10^-3 nmol/L/mg. Conclusion A novel method discriminating between good and poor adherence to simvastatin therapy in CHD patients has been developed. The sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurements in spot blood samples, according to specific cut-off values. Abstract Figure 1 Drug levels vs dose avoidance

Effect of Pomelo Juice on the Pharmacokinetics of Simvastatin, CYP3A2 Activity and Mdr1a, Mdr1b and Slc21a5 Expressions in Rats

Background: Food-drug interaction can decrease drug effectiveness or increase risk of drug toxicity. Simvastatin is widely used for treatment of hypercholesterolemia and hypertriglyceridemia. Therefore, this study aimed to investigate the effects of pomelo juice on the pharmacokinetics of simvastatin, CYP3a2 activity and Mdr1a, Mdr1b and Slc21a5 expressions in rats. Methods: Rats were divided into 4 groups including (i) control, (ii) pomelo that received pomelo juice orally twice daily for 7 days, (iii) simvastatin that received simvastatin on day 8, and (iv) simvastatin + pomelo juice. Plasma concentrations of simvastatin and simvastatin acid were analyzed using LC-MS/MS. Hepatic CYP3a2 activity was evaluated using midazolam hydroxylation assay. The expressions of hepatic and intestinal Mdr1a, Mdr1b and Slc21a5 were measured using the real-time RT-PCR. Results: Oral administration of pomelo juice for 7 days altered pharmacokinetic profiles of simvastatin and its primary active metabolite, simvastatin acid, in rats. Real-time RT-PCR analysis revealed that pomelo juice significantly suppressed the expression of intestinal Mdr1a and Mdr1b and hepatic Slc21a5. Rat hepatic CYP3a2 catalytic activity was also inhibited following pomelo juice administration. Conclusion: The results of this study suggested that there was a risk of potential drug interaction associated with inhibition of drug transporters and CYP3A caused by pomelo juice.

Effect of Cilostazol on the Pharmacokinetics of Simvastatin in Healthy Subjects

Purpose. We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. Methods. An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. Results. The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. Conclusions. Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.