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Effect of Clopidogrel on the Steady-State Pharmacokinetics of Fluvastatin

From Novartis Pharmaceuticals, East Hanover, New Jersey.

Address for reprints: Address for correspondence: Surya P. Ayalasomayajula, PhD, Novartis Pharmaceuticals, One Health Plaza, East Hanover, NJ 07936; e-mail: surya.ayalasomayajula{at}novartis.com.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study assessed the effects of clopidogrel, a CYP 2C9 inhibitor, on fluvastatin pharmacokinetics in healthy volunteers. The effects of combined clopidogrel-fluvastatin treatment on platelet function were also determined. Subjects received 80 mg fluvastatin (extended-release formulation) alone on days 1 through 9, 80 mg fluvastatin and 300 mg clopidogrel (loading dose) on day 10, and 80 mg fluvastatin and 75 mg clopidogrel (maintenance dose) on days 11 through 19. Compared to treatment with fluvastatin alone, fluvastatin AUC was similar and C_max increased marginally (15.7%) with concomitant treatment with clopidogrel. Platelet aggregation was inhibited by clopidogrel by 33% two hours after the loading dose and by 47% at steady state, similar to that reported for clopidogrel alone treatment. The authors conclude that coadministration of fluvastatin and clopidogrel has no clinically relevant effect on fluvastatin pharmacokinetics or on platelet inhibition by clopidogrel.

Key Words: Clopidogrel • fluvastatin • pharmacokinetics • drug interactions

Fluvastatin is absorbed rapidly and completely following oral administration. The absolute bioavailability following administration of 10 mg fluvastatin is 19% to 29%, and bioavailability is dose dependent. Fluvastatin undergoes extensive first-pass hepatic extraction and is metabolized by CYP 450 enzymes. The metabolites do not circulate systemically and are eliminated in the bile. CYP 2C9 accounts for 50% to 80% of fluvastatin metabolism, whereas CYP 2C8 and CYP 3A4 play only a minor role in metabolic clearance. About 90% of fluvastatin is eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%.⁸ The plasma elimination half-life of fluvastatin is approximately 2.5 hours following oral administration of an immediate-release formulation. Administration of an extended-release tablet formulation increased the apparent terminal half-life of fluvastatin to 10.8 hours, permitting once-daily dosing.

Clopidogrel is an antiplatelet agent that is frequently coadministered with HMG-CoA reductase inhibitors (statins). Clopidogrel inhibits adenosine diphosphate (ADP)-induced platelet aggregation by direct inhibition of ADP binding to its receptor (P2Y12).

Clopidogrel is a prodrug that is metabolized by hydrolysis to its carboxylic acid, an inactive metabolite, following oral administration. The carboxylic acid derivative, which represents about 85% of the circulating metabolites in plasma, is eliminated with an estimated half-life of 7 to 8 hours. Clopidogrel plasma levels are below the detection limits within 2 hours after oral administration. The pharmacological activity of clopidogrel is mediated by the formation of the thiol metabolite of clopidogrel, which is formed by CYP 3A4 enzyme activity.⁹ Therefore, statins that are metabolized by CYP 3A4 (atorvastatin, simvastatin, and lovastatin) could have potential interactions with clopidogrel when coadministered.^10,11 The onset of inhibition of platelet aggregation by clopidogrel is dose dependent and can be observed within 2 hours after a single oral dose.¹² Steady-state inhibition of platelet aggregation by clopidogrel is reached following 3 to 7 days of daily administration of 75 mg.¹²

Clopidogrel at a concentration of 10 µM was shown to inhibit CYP 2C9 activity by 53% in vitro, using recombinant CYP 450 enzymes.¹³ Because fluvastatin is predominantly metabolized by CYP 2C9, there is the potential for an increase in fluvastatin exposure when coadministered with clopidogrel. Thus, the current study was conducted to investigate the potential for a pharmacokinetic drug-drug interaction between fluvastatin and clopidogrel. In addition, the effects on platelet function of clopidogrel in the presence of fluvastatin are also assessed.

	METHODS

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Study Design
This study employed an open-label, multiple-dose, sequential design. After screening, 30 healthy male volunteers were enrolled to ensure that at least 24 subjects would complete the study. All subjects provided written informed consent prior to participating in the study and were not to have any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of any drug. The assessment of background and demographic data included medical history, current medical conditions, date of birth, sex, race, height, elbow breadth, and frame size. Subjects were screened for drugs of abuse (alcohol, cannabinoids, cocaine, and opiates), hepatitis B and C, HIV, and cotinine. Safety assessments included monitoring and recording all observed and reported adverse events, blood chemistry, hematologic profile, urine analysis, electrocardiogram (ECG) recordings, measurements of vital signs, and physical examinations.

Subjects between the ages of 19 and 45 years, in good health as determined by medical history, physical examination, ECG, and laboratory tests, were included in the study. The subjects were admitted to the study center for baseline evaluation at least 12 hours prior to initial dosing of fluvastatin. Subjects were discharged from the study center on day 1 and returned on the evening of day 4. Subjects were confined to the study center for the remainder of the study (days 4-19).

On study days 1 through 19, subjects received 80 mg fluvastatin extended-release formulation (Lescol XL) daily by mouth. On day 10, a loading dose of 300 mg clopidogrel was coadministered with fluvastatin. Fluvastatin and 75 mg clopidogrel were coadministered daily on study days 11 through 19. Study medication was administered by the study center personnel with 240 mL of water between 0730 and 0900, after at least a 10-hour fast. All subjects were dosed within a maximum of a 1-hour interval. Subjects were instructed not to chew the medication but to swallow it whole. The investigator checked each subject's mouth to ensure that the medication was swallowed. Unless performing a study assessment, subjects rested in the upright position for the next 4 hours.

The study protocol was approved by MDS Pharma Services Institutional Review Board (Lincoln, Neb, USA). Following the approval, the study was conducted at SFBC International, (Miami, Fla, USA) in accordance with the Declaration of Helsinki and the US code of federal regulations.

Pharmacokinetic Sample Collection
For the determination of serum concentrations of fluvastatin, 3-mL predose blood samples were collected into serum separator tubes on days 7, 8, 17, and 18. Serial blood samples were collected on days 9 and 19 at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose. All samples were collected by either direct venipuncture or by an indwelling cannula inserted in a forearm vein. The samples were protected from direct sunlight and ultraviolet (UV) irradiation. The samples were centrifuged at 800 g for 15 minutes between 3°C and 5°C. The serum was separated, and samples were frozen at -20°C for determination of fluvastatin concentration. At the time of conducting this study, no sensitive bioanalytical method was available to measure plasma clopidogrel concentrations at a steadystate therapeutic dose (75 mg). Therefore, to assess the fluvastatin effect on clopidogrel, ADP-induced platelet aggregation and bleeding time were measured (see Pharmacodynamic Assessments).

Fluvastatin Analysis
Serum concentrations of fluvastatin were measured using high-performance liquid hromatography/tandem mass spectrometry (LC/MS/MS). A liquid chromatographic/tandem mass-spectrometric method is described for the determination of fluvastatin in human serum. Of the internal standard (450 ng/mL of IS_XUO320 in 2.25% methanol), 50 µL was added to 100-µL serum samples, which were thoroughly mixed and extracted using liquid partitioning with acetonitrile and saturated aqueous sodium chloride solution. The separation of analytes was achieved on a WATERS XTerra RP18 column (3.0 x 50 mm, 3.5 µm) with a mobile phase consisting of 0.1% acetic acid/methanol (35:65, v/v) at an isocratic flow rate of 0.5 mL/min. The sample injector was then washed 3 times with mobile phase and 3 times with acetonitrile after each sample injection. Detection of analytes was accomplished using turbo ion spray (TIS) negative ionization (API4000) with the collision energy set at -20 V (ion spray voltage of -4500 V) while keeping the ceramic heater temperature at 700°C. The parent compound has a selected m/z ratio of 410.2 for the precursor and 348.2 for the product. The internal standard has a selected m/z ratio of 424.2 for the precursor and 362.0 for the product. Appropriate calibration standards and quality control samples were used in the analytical procedure. The analytical data were captured using WATSON LIMS (Version 6.2.0.02 [EC] ) software. The limit of quantitation was 2.0 ng/mL. The assay was validated within a concentration range of 2 to 2000 ng/mL. The accuracy and precision (percentage coefficient of variation [%CV]) for calibration, intraday, and interday samples ranged from 96.0% to 112.0% and 1.1% to 17.2%, respectively. The stability of fluvastatin was ensured for at least 4.5 months at -20°C, for at least 3 freeze-thaw cycles, and for at least 24 hours at room temperature in human serum.

Pharmacodynamic Assessments
The pharmacodynamic effect of clopidogrel in combination with fluvastatin was assessed by measuring inhibition of ADP-induced platelet aggregation and prolongation of template bleeding time. Blood samples (5 mL/sample) were collected into tubes containing sodium citrate at 2 hours postdosing on day 9 (prior to initiation of clopidogrel administration); on days 10, 12, 14, 16, and 19 (fluvastatin and clopidogrel); and on day 24 (end of study). The blood samples were centrifuged at 100 g for 15 minutes to obtain platelet-rich plasma (PRP). The platelet count in PRP was adjusted to 250 000/mL. The remaining sample was further centrifuged at 3000 rpm for 15 minutes to obtain platelet-poor plasma (PPP), which was used as subject blank. Platelet aggregation was induced by 5 µM ADP, and optical density was measured using a Chrono-log Optical Aggregometer (Model 490-4DR with internal AGGRO/LINK interface and Windows software Version 5.1 or higher). The bleeding time was measured using the Ivy method.¹⁴

Pharmacokinetic Assessments
Pharmacokinetic parameters were calculated using serum fluvastatin concentrations by noncompartmental methods (WinNonlin Pro Version 4.1, Pharsight Corporation, Mountain View, Calif, USA). The pharmacokinetic parameters included C_max (maximum concentration observed postdose), C_trough (observed predose concentration), t_max (time to C_max), and AUC (area under the concentration-time curve [AUC] from 0 to the time of the dosing interval).

Statistical Analysis
All subjects who completed the study with evaluable pharmacokinetic and pharmacodynamic measurements were included in the data analysis.

Pharmacokinetics
Fluvastatin pharmacokinetic parameters C_max and AUC obtained on day 19 (fluvastatin + clopidogrel) and day 9 (fluvastatin alone) were analyzed. Statistical analyses were performed on log-transformed parameter values, using SAS Version 8.2. Each parameter was analyzed using a linear mixed-effect model, and log-mean differences of treatment fluvastatin + clopidogrel minus fluvastatin and corresponding 90% confidence intervals (CIs) were calculated. These were back-transformed and reported in the original scale.

Pharmacodynamics
Percentage of ADP-induced platelet aggregation and bleeding time during treatment with fluvastatin + clopidogrel (days 10 through 19) and end of study (day 24) were compared with fluvastatin alone (day 9) using a linear mixed-effect model. For bleeding time, the log-transformed data were used. All pharmacokinetic and pharmacodynamic parameters during combined treatment with fluvastatin and clopidogrel were compared with fluvastatin alone (day 9).

	RESULTS

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Demographics, Safety, and Tolerability
A total of 30 healthy male volunteers who were aged 33.3 ± 7 years, weighed 76.5 ± 10 kg, and had a height of 173.3 ± 7 cm were enrolled into the study. Of the enrolled subjects, 2 were Caucasian (6.7%), 4 were African American (13.3%), and 24 (80%) were of other race/ethnicity (primarily Hispanic). No subjects of Asian descent were enrolled into the study.

A total of 5 adverse events were reported by 4 subjects: nasal congestion, elevated creatine kinase (2 subjects), and constipation (reported twice by the same subject). All adverse events were considered mild in severity, and none compromised the safety of participants. Four of 5 adverse events were considered unrelated to the study drug, and 1 (elevated creatine kinase) was presumed to be related to the study drug. Six subjects discontinued from the study. One subject had an elevated creatine kinase value on day 10, and another subject had an elevated creatine kinase value on day 4 from the initiation of study dosing. Both subjects indicated they had performed strenuous exercise while participating in the study (protocol violation) and were discontinued. At the end of study evaluations, creatine kinase values for both subjects were within normal range. Two subjects withdrew their consent. One subject tested positive in the drug test screen and was discontinued. One subject did not follow up for the study. Pharmacokinetic and pharmacodynamic data obtained from 24 subjects who completed all study procedures were included in the data analysis.

Effects of Clopidogrel on the Pharmacokinetics of Fluvastatin
The steady-state plasma concentration-time profiles of fluvastatin, when administered alone or in combination with clopidogrel, were similar, as shown in Figure 1. The derived pharmacokinetic parameters are presented in Table I. Coadministration of fluvastatin with clopidogrel resulted in an increase in fluvastatin C_max from 64.48 ng/mL (fluvastatin alone) to 71.15 ng/mL (coadministration with clopidogrel). The geometric mean ratio for C_max was 1.27 (P = .018). There was no effect of clopidogrel on fluvastatin AUC. The individual values for fluvastatin C_max and AUC for subjects treated with fluvastatin alone (day 9) and in combination with clopidogrel (day 19) are shown in Figure 2. Clopidogrel had no effect on the median t_max of fluvastatin, suggesting no influence of clopidogrel on fluvastatin absorption rate. The apparent half-life for fluvastatin (extended-release formulation) was similar when administered alone or in combination with clopidogrel.

View larger version (10K): [in this window] [in a new window]   Figure 1. Steady-state concentration-time profile following multiple-dose administrations of 80 mg fluvastatin (extended-release formulation) with and without clopidogrel. Fluvastatin alone (solid square) and fluvastatin + clopidogrel (open circle). Data are mean (SD), n = 24.

View larger version (10K): [in this window] [in a new window]   Figure 2. Individual Cmax and AUC values for fluvastatin following multiple-dose administration of 80 mg fluvastatin (extended-release formulation) with and without clopidogrel.

The mean predose (C_min) concentrations of fluvastatin prior to clopidogrel administration (days 7, 8, and 9) and following clopidogrel administration (days 17, 18, and 19) are presented in Figure 3. Fluvastatin plasma concentration reached steady state by day 7, and clopidogrel had no effect on the steady-state levels.

View larger version (7K): [in this window] [in a new window]   Figure 3. Mean predose concentrations (Ctrough) of fluvastatin following multiple-dose administration of 80 mg fluvastatin (extended-release formulation) with and without clopidogrel.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Fluvastatin is a potent HMG-CoA reductase inhibitor that is predominantly metabolized by CYP2C9.¹⁵ Clopidogrel is an irreversible ADP receptor (P2Y12) antagonist that inhibits CYP2C9 activity in vitro,¹³ raising the possibility of a potential drug-drug interaction between fluvastatin and clopidogrel. Therefore, this study examined the effect of clopidogrel on the pharmacokinetics of fluvastatin and also determined the extent of platelet inhibition (ADP-induced aggregation) by clopidogrel in the presence of therapeutic concentrations of fluvastatin.

The main finding in this study was that clopidogrel had no significant effect on fluvastatin exposure (AUC), although there was a small but statistically significant increase in C_max (Table I). The variability in fluvastatin pharmacokinetics observed in this study is similar to that reported in earlier studies.¹⁶ The magnitude of effect of clopidogrel on fluvastatin C_max (ratio of geometric means 1.27) was similar to the estimated coefficient of variation for C_max (31.6%) and is not considered to be clinically relevant. The absence of any major effect of clopidogrel on fluvastatin pharmacokinetics in this study indicates that clopidogrel at therapeutic concentrations does not significantly inhibit CYP 2C9 in vivo.

In vitro studies indicate that clopidogrel inhibits CYP 2C9 activity by 53% at a concentration of 10 µM.¹³ Oral administration of high-dose clopidogrel (600 mg), which is approximately 8-fold higher than the recommended therapeutic maintenance dose, resulted in a mean C_max of 38.0 ng/mL (0.9 µM).¹⁷ The pharmacokinetics of clopidogrel are shown to be dose linear between the 300- and 600-mg doses.¹⁸ Assuming linear pharmacokinetics for clopidogrel between the 75- and 600-mg doses, the predicted C_max for clopidogrel at the 75-mg dose (4.75 ng/mL) is 40-fold lower than CYP 2C9 inhibitory concentrations. We have confirmed that high concentrations of clopidogrel (60 µM) are required to inhibit fluvastatin metabolism by 50% in human liver microsomes (unpublished data).

The pharmacodynamic effects of clopidogrel in the presence of fluvastatin were determined by measuring ADP (5 µM)-induced platelet aggregation and bleeding time. Clopidogrel was observed to inhibit platelet aggregation by 33% within 2 hours following administration of a loading dose of 300 mg and by 47% following 3 days of maintenance doses of 75 mg (Table II). Although we did not measure the effect of clopidogrel alone on ADP-induced platelet aggregation, the magnitude of inhibition in the presence of therapeutic concentrations of fluvastatin was similar to that reported for clopidogrel administered alone using the same dosing regimen.¹²

Bleeding time also increased during combined treatment with clopidogrel and fluvastatin. Despite the large variability in bleeding time measurements and the relatively small number of subjects, observed increases were statistically significant on days 16 and 19 compared to day 9 (baseline), providing further evidence for platelet inhibition.

Mach et al¹⁹ recently reported a small but statistically significant decrease in ADP-induced platelet aggregation when fluvastatin was coadministered with clopidogrel. The authors hypothesized that clopidogrel increases fluvastatin concentrations by inhibiting CYP2C9 and that increased fluvastatin then inhibits CYP3A4, resulting in decreased formation of the active clopidogrel metabolite. In the absence of any significant effect of clopidogrel on fluvastatin exposure, the hypothesized effect of fluvastatin on clopidogrel-mediated platelet aggregation cannot be explained. Although the interindividual variability for the inhibition of platelet aggregation observed in our study was comparable to previously published reports,^12,20 the variability in the study by Mach et al¹⁹ was not reported, making direct comparison of results difficult. In addition, the maximum observed C_max value of fluvastatin in the presence of clopidogrel in this study (114.0 ng/mL, 0.26 µM) is well below the k_i value (94.3 µM) for CYP3A4 inhibition.²¹ Therefore, at clinical doses, it is highly unlikely that fluvastatin inhibits CYP3A4 activity.

One potential limitation of this study is that we did not evaluate the CYP 2C9 genotype.

In conclusion, the combination of fluvastatin with clopidogrel did not significantly alter fluvastatin pharmacokinetics. Inhibition of ADP-induced platelet aggregation by clopidogrel in combination with fluvastatin was similar to that reported for clopidogrel alone. We conclude that fluvastatin and clopidogrel can be safely coadministered with no need for dosage adjustment.

	ACKNOWLEDGEMENTS

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The authors sincerely acknowledge Chaitanya Joshi (SAS programmer), Sarita Kannarath (SAS programmer), and Selene Leon, PhD, for their contributions to the data management and statistical analysis of the pharmacodynamic parameters, and the contribution of Tomoyoshi Naganuma.

Financial disclosure: All authors are employees of Novartis Pharmaceuticals.

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TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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