The Difference in Pharmacokinetics and Pharmacodynamics between Extended-Release Fluvastatin and Immediate-Release Fluvastatin in Healthy Chinese Subjects

The aim of this study was to evaluate the difference in pharmacokinetics and pharmacodynamics between extended-release (ER) fluvastatin tablet and its immediate-release (IR) capsule in Chinese healthy subjects. This was an open-label, single/multiple-dose, two-period, two-treatment, crossover, randomized trial with a minimum washout period of 7 days. Twenty healthy male adult subjects were given fluvastatin ER tablet 80 mg QD by oral administration or fluvastatin IR capsule 40 mg BID for seven days. Blood samples were collected up to 24 hours after dosing on day 1 and day 7. Serum concentrations of fluvastatin were determined by LC-MS/MS. For fluvastatin ER tablet 80 mg QD, Cmax was 61.0 ± 39.0 and 63.9 ± 29.7 ng/mL, and AUC0−24 h was 242 ± 156 and 253 ± 91.1 ng·h/mL on day 1 and 7, respectively. For fluvastatin IR capsule 40 mg BID, Cmax was 283 ± 271 and 382 ± 255 ng/mL, and AUC0−24 h was 720 ± 776 and 917 ± 994 ng·h/mL on day 1 and day 7, respectively. The relative bioavailability of fluvastatin ER tablet 80 mg QD to fluvastatin IR capsule 40 mg BID is (45.3 ± 23.9)% and (43.3 ± 24.1)% on day 1 and day 7, respectively. Tmax for fluvastatin ER tablet was 2.50 and 2.60 h and for capsule was 0.78 and 0.88 h on day 1 and day 7, respectively. In the first period, compared to baseline, cholesterol decreased 15.3% in fluvastatin ER tablet 80 mg QD and 16.9% in fluvastatin IR capsule 40 mg BID. Triglyceride decreased 3.7% in fluvastatin ER tablet 80 mg QD and 19.1% in fluvastatin IR capsule 40 mg BID. The difference has no statistical significance at P > 0.05 in reduction percent of cholesterol and triglyceride between the two groups. No adverse events were recorded. The results indicated that Cmax of fluvastatin ER tablet is reduced and Tmax is prolonged compared with IR capsule. There is no accumulation for ER formulation after multiple doses.


Introduction
Fluvastatin, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is the first fully synthetic HMG-CoA reductase inhibitor and the well-established first-line agent for the treatment of hypercholesterolemia, primarily due to its marked lowering action of low-density lipoprotein cholesterol (LDL-C) levels (as discussed by Bruckert et al. [1]). The benefits of statin therapy on cardiovascular morbidity and mortality are thought to be related to both LDL-C lowering and pleiotropic effects such as modulation of inflammatory protein levels (as discussed elsewhere [2,3]). Small increases in HDL-C and variable decrease in TG are also observed.
Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolized in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites (as discussed by Scripture and pieper [4]). An ER formulation of fluvastatin was developed as a starting and maintenance treatment for once-daily administration. It uses a hydrophilic cellulose matrix that swells when it is in contact with fluid in the intestine. Fluvastatin then diffuses through the matrix and is released over an 8-hour period. It was hypothesized that 2 Journal of Biomedicine and Biotechnology   this new formulation would avoid hepatic saturation without elevating systemic drug levels and thus provide greater efficacy compared with the conventional formulation (as discussed elsewhere [5,6]). Fluvastatin ER tablet 80 mg/d has been reported to provide comprehensive lipid management with a good safety profile similar to that of placebo in clinical trials (as discussed by Battantyne et al. [7]).
The pharmacokinetic properties of two fluvastatin formulations have been investigated in healthy white adult subjects (as discussed by Isaacsohn et al. [5]). Fluvastatin systemic exposure was less than 50% when administered as fluvastatin ER 80 mg qd compared with fluvastatin IR 40 mg BID (as discussed by Barilla et al. [6]). There is no pharmacokinetic data for fluvastatin ER tablet in Chinese subjects.
The purpose of the present study was to evaluate the difference in pharmacokinetics and pharmacodynamics between extended-release (ER) fluvastatin tablet and its immediate-release (IR) capsule after single and multiple doses in Chinese healthy subjects living in China. The study was conducted in accordance with the regulatory requirements for registration in China.

Study Populations.
Twenty healthy male adult subjects were invited to participate in an open-label, randomized, single and multiple dose, two-period, two-treatment, crossover study. At the time of enrolment, the subjects were informed of the purpose, duration, and risks of the study, and they were requested to sign a written informed consent. They were also informed about the possibility of withdrawing from the study. They were prohibited to take food that contains xanthine or beverages from 48 h prior to the study until the end of the study. The subjects were also instructed to abstain from taking any medication except paracetamol in 2 weeks prior to the study. The evaluations and tests performed included physical examination, body height, body weight, vital signs (heart rate, systolic and diastolic blood pressure, and body temperature), hematology, blood chemistry, urinalysis, and electrocardiogram. The subjects were requested to report any abnormality occurring throughout and after the study. The results of clinical evaluations were documented in individual case report forms. The study protocol was approved by the Ethics Committee of Zhongshan Hospital.

Study Design.
Healthy subjects were randomized in two groups of ten subjects, and each group received the two drug treatments at two different periods, with a 7-day interdose washout periods. Each volunteer received fluvastatin ER tablet 80 mg QD or fluvastatin IR capsule 40 mg BID for seven days. Each formulation was administered with 200 mL of water to subjects after a 10 h overnight fasting. Lunch and dinner were served at 4 and 10 h after dose, respectively. If the subject is receiving the fluvastatin IR BID treatment, the evening dose of fluvastatin IR 40 mg will be administered 12 hours following the morning dose. The evening meal should be consumed 3 hours prior to this dose. Blood samples were collected through an intravenous catheter in the Lescol IR 40 mg group before dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 12.5, 13, 14, 16, 20, and 24 h after dose on day 1 and day 7. And for fluvastatin 80 mg ER tablet group, blood samples were drawn prior to dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 h following dose on day 1 and day 7. The blood samples were transferred to tubes and centrifuged (4 • C) at 800 rpm for 15 min. The serum samples were stored at -20 • C until chromatographic analysis.   ) is calculated as C av = AUC 0−τ /τ. The C max and T max were obtained directly from the data. The degree of peak-trough fluctuation at steady state (DF) was calculated using the following equation: DF(%) = (C max,ss − C min,ss )/C av,ss × 100%, where C max,ss , C min,ss , and C av,ss are the maximum, minimum, and average serum concentration, respectively, during a dosing interval at steady state. The accumulation ratio (R) was calculated as C max,ss /C max . An accumulation ratio of 1 indicated no or minimal accumulation. Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and was performed using the F ratio, where F was the ratio of AUC 0−24 for fluvastatin ER tablet versus fluvastatin IR capsule. Ratios of ln(C max ) and ln (AUC 0−t ) for all formulations were calculated, and 90% CIs were obtained. An analysis of variance (ANOVA, SPSS16.0) for cholesterol and triglyceride was carried out to evaluate the pharmacodynamic difference between fluvastatin ER tablet and fluvastatin IR capsule after continuous 7-day administration.
Mean serum concentration-time curves of fluvastatin formulations on day 1 and day 7 are shown in Figures  1 and 2, and the pharmacokinetic properties (C max , T max , MRT, AUC 0−24 ) are summarized in Table 1. Ninety percent confidence intervals of AUC 0−24 ratios were 0.306, 0.494 (ratio 0.388) and 0.293, 0.466 (ratio 0.370) for fluvastatin ER tablet versus fluvastatin IR capsule on day 1 and at day 7, respectively. Ninety percent confidence intervals of C max ratios were 0.184, 0.376 (ratio 0.263) and 0.158, 0.233 (ratio 0.192) for fluvastatin ER tablet versus fluvastatin IR capsule on day 1 and at day 7, respectively.

Pharmacodynamic
Results. The mean baseline of cholesterol and triglyceride of ten subjects who received fluvastatin ER tablet once daily first was 3.70 ± 0.70 and 0.67 ± 0.16 mmol/l. The mean reduction of cholesterol and triglyceride after continuous 7-day administration was 0.58 ± 0.24 and 0.05±0.16 mmol/l, respectively. The percent of reduction was 15.3 ± 5.4% and 3.7 ± 19.8%, respectively. The mean baseline of cholesterol and triglyceride of ten subjects who received fluvastatin IR capsule twice daily first was 3.84±0.87 and 0.87 ± 0.39 mmol/l. The mean reduction of cholesterol and triglyceride after continuous 7-day administration was 0.71 ± 0.56 and 0.23 ± 0.31 mmol/l, respectively. The percent of reduction was 16.9±11.2% and 19.1±20.4%, respectively. The difference has no statistical significance at P > 0.05 in baseline of cholesterol and triglyceride between group of 80 mg fluvastatin ER tablet and group of 40 mg fluvastatin IR capsule. The difference has also no statistical significance at P = 0.681 and P = 0.104 in reduction percent of cholesterol and triglyceride between the two groups, respectively.

Tolerability.
No adverse events occurred throughout the study.
3.4. Discussion. The ER formulation of fluvastatin was developed to decrease the frequency of dose administration and to reduce the incidence of AEs by reducing peak serum concentrations after drug administration. Because these concentrations may be related to the extent in which patients experience common AEs, the use of an ER formulation may help reduce these effects and improve tolerability.
Results from the single and multiple dose study showed that in Chinese healthy subjects, the mean C max of 80 mg fluvastatin ER tablet once daily at single dose and multiple doses was 61.0 and 63.9 ng/mL, which was 78.4% and 83.3% lower compared with that of 40 mg fluvastatin IR capsule twice daily at single dose and multiple doses, respectively. The mean exposure with ER tablet (single dose and multiple dose AUC 0−24 h ) was 242 and 253 ng·h/mL, which were 66.4% and 72.5% lower compared with IR capsule, respectively. However, the difference has no statistical significance at P > 0.05 in reduction percent of cholesterol and triglyceride between group of 80 mg fluvastatin ER tablet and group of 40 mg fluvastatin IR capsule. The possible reason was that the time of effective concentration for 80 mg fluvastatin ER was no shorter than that for 40 mg fluvastatin IR.
The peak concentration was delayed for ER formulation of fluvastatin. In addition, there was less fluctuation from C max to C min for ER formulation of fluvastatin compared with IR formulation of fluvastatin.

Conclusion
The LC-tandem mass spectrometry method established for the determination of fluvastatin in human serum following administration of fluvastatin is simple, rapid, and showed to be highly reproducible and accurate. Compared with immediate-release formulation, C max of fluvastatin extended-release tablet is reduced and T max is prolonged, respectively. There is no accumulation for extended-release formulation after multiple doses. The difference has no statistical significance at P > 0.05 in reduction percent of cholesterol and triglyceride between the two groups. Fluvastatin was well tolerated following single and multiple doses.