The Journal of Clinical

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Effect of Clopidogrel on the Steady-State Pharmacokinetics of Fluvastatin

Surya P. Ayalasomayajula, Sujata Vaidyanathan, Charisse Kemp, Pratapa Prasad, Alfred Balch and William P. Dole

J. Clin. Pharmacol. 2007; 47; 613

DOI: 10.1177/0091270006299138

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 Effect of Clopidogrel on the Steady-State
Pharmacokinetics of Fluvastatin
Surya P. Ayalasomayajula, PhD, Sujata Vaidyanathan, PhD,
Charisse Kemp, BS, Pratapa Prasad, PhD, Alfred Balch, PhD,
and William P. Dole, MD

This study assessed the effects of clopidogrel, a CYP 2C9 Platelet aggregation was inhibited by clopidogrel by 33%
inhibitor, on fluvastatin pharmacokinetics in healthy volun- two hours after the loading dose and by 47% at steady state,
teers. The effects of combined clopidogrel-fluvastatin treat- similar to that reported for clopidogrel alone treatment. The
ment on platelet function were also determined. Subjects authors conclude that coadministration of fluvastatin and
received 80 mg fluvastatin (extended-release formulation) clopidogrel has no clinically relevant effect on fluvastatin
alone on days 1 through 9, 80 mg fluvastatin and 300 mg pharmacokinetics or on platelet inhibition by clopidogrel.
clopidogrel (loading dose) on day 10, and 80 mg fluvastatin
and 75 mg clopidogrel (maintenance dose) on days 11 Keywords: Clopidogrel; fluvastatin; pharmacokinetics;
through 19. Compared to treatment with fluvastatin alone, drug interactions
fluvastatin AUC was similar and Cmax increased margin- Journal of Clinical Pharmacology, 2007;47:613-619
ally (15.7%) with concomitant treatment with clopidogrel. ©2007 the American College of Clinical Pharmacology

F luvastatin is a competitive inhibitor of HMG-

CoA reductase, the rate-limiting enzyme in cho-
lesterol biosynthesis. Fluvastatin is commercially
following administration of 10 mg fluvastatin is
19% to 29%, and bioavailability is dose dependent.
Fluvastatin undergoes extensive first-pass hepatic
available as an immediate-release formulation and extraction and is metabolized by CYP 450 enzymes.
extended-release formulation. Fluvastatin is effective The metabolites do not circulate systemically and
in reducing total cholesterol, low-density lipopro- are eliminated in the bile. CYP 2C9 accounts for
tein cholesterol, and triglycerides and in increasing 50% to 80% of fluvastatin metabolism, whereas CYP
high-density lipoprotein cholesterol in patients with 2C8 and CYP 3A4 play only a minor role in meta-
primary hypercholesterolemia and mixed dyslipi- bolic clearance. About 90% of fluvastatin is elimi-
demia.1-3 Fluvastatin has been shown to be effective nated in the feces as metabolites, with less than 2%
in lowering cholesterol and to be safe and well tol- present as unchanged drug. Urinary recovery is about
erated. In addition to its lipid-modulating effects, 5%.8 The plasma elimination half-life of fluvastatin is
fluvastatin, like other HMG-CoA reductase inhibitors, approximately 2.5 hours following oral administration
possesses anti-inflammatory properties that might of an immediate-release formulation. Administration
contribute to its antiatherogenic effects in experi- of an extended-release tablet formulation increased
mental models independent of lipid lowering.4-7 the apparent terminal half-life of fluvastatin to 10.8
Fluvastatin is absorbed rapidly and completely fol- hours, permitting once-daily dosing.
lowing oral administration. The absolute bioavailability Clopidogrel is an antiplatelet agent that is frequently
coadministered with HMG-CoA reductase inhibitors
(statins). Clopidogrel inhibits adenosine diphosphate
From Novartis Pharmaceuticals, East Hanover, New Jersey. Submitted for (ADP)–induced platelet aggregation by direct inhibi-
publication September 12, 2006; revised version accepted December 27,
2006. Address for correspondence: Surya P. Ayalasomayajula, PhD,
tion of ADP binding to its receptor (P2Y12).
Novartis Pharmaceuticals, One Health Plaza, East Hanover, NJ 07936; Clopidogrel is a prodrug that is metabolized by
e-mail: surya.ayalasomayajula@novartis.com. hydrolysis to its carboxylic acid, an inactive metabo-
DOI: 10.1177/0091270006299138 lite, following oral administration. The carboxylic

J Clin Pharmacol 2007;47:613-619 613

 AYALASOMAYAJULA ET AL

acid derivative, which represents about 85% of the physical examination, ECG, and laboratory tests, were
circulating metabolites in plasma, is eliminated with included in the study. The subjects were admitted to
an estimated half-life of 7 to 8 hours. Clopidogrel the study center for baseline evaluation at least 12
plasma levels are below the detection limits within hours prior to initial dosing of fluvastatin. Subjects
2 hours after oral administration. The pharmacolog- were discharged from the study center on day 1 and
ical activity of clopidogrel is mediated by the forma- returned on the evening of day 4. Subjects were con-
tion of the thiol metabolite of clopidogrel, which is fined to the study center for the remainder of the
formed by CYP 3A4 enzyme activity.9 Therefore, study (days 4-19).
statins that are metabolized by CYP 3A4 (atorvastatin, On study days 1 through 19, subjects received 80
simvastatin, and lovastatin) could have potential mg fluvastatin extended-release formulation (Lescol
interactions with clopidogrel when coadministered.10,11 XL) daily by mouth. On day 10, a loading dose of
The onset of inhibition of platelet aggregation by 300 mg clopidogrel was coadministered with fluvas-
clopidogrel is dose dependent and can be observed tatin. Fluvastatin and 75 mg clopidogrel were coad-
within 2 hours after a single oral dose.12 Steady-state ministered daily on study days 11 through 19. Study
inhibition of platelet aggregation by clopidogrel is medication was administered by the study center
reached following 3 to 7 days of daily administration personnel with 240 mL of water between 0730 and
of 75 mg.12 0900, after at least a 10-hour fast. All subjects
Clopidogrel at a concentration of 10 µM was were dosed within a maximum of a 1-hour interval.
shown to inhibit CYP 2C9 activity by 53% in vitro, Subjects were instructed not to chew the medication
using recombinant CYP 450 enzymes.13 Because flu- but to swallow it whole. The investigator checked
vastatin is predominantly metabolized by CYP 2C9, each subject’s mouth to ensure that the medication
there is the potential for an increase in fluvastatin was swallowed. Unless performing a study assess-
exposure when coadministered with clopidogrel. ment, subjects rested in the upright position for the
Thus, the current study was conducted to investi- next 4 hours.
gate the potential for a pharmacokinetic drug-drug The study protocol was approved by MDS Pharma
interaction between fluvastatin and clopidogrel. In Services Institutional Review Board (Lincoln, Neb,
addition, the effects on platelet function of clopido- USA). Following the approval, the study was con-
grel in the presence of fluvastatin are also assessed. ducted at SFBC International, (Miami, Fla, USA) in
accordance with the Declaration of Helsinki and the
METHODS US code of federal regulations.

Study Design Pharmacokinetic Sample Collection

This study employed an open-label, multiple-dose, For the determination of serum concentrations of
sequential design. After screening, 30 healthy male vol- fluvastatin, 3-mL predose blood samples were col-
unteers were enrolled to ensure that at least 24 subjects lected into serum separator tubes on days 7, 8, 17,
would complete the study. All subjects provided writ- and 18. Serial blood samples were collected on days
ten informed consent prior to participating in the study 9 and 19 at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,
and were not to have any surgical or medical condition 10, 12, 16, and 24 hours postdose. All samples were
that might significantly alter the absorption, distribu- collected by either direct venipuncture or by an
tion, metabolism, or excretion of any drug. The assess- indwelling cannula inserted in a forearm vein. The
ment of background and demographic data included samples were protected from direct sunlight and
medical history, current medical conditions, date of ultraviolet (UV) irradiation. The samples were cen-
birth, sex, race, height, elbow breadth, and frame size. trifuged at 800 g for 15 minutes between 3°C and
Subjects were screened for drugs of abuse (alcohol, 5°C. The serum was separated, and samples were
cannabinoids, cocaine, and opiates), hepatitis B and C, frozen at –20°C for determination of fluvastatin con-
HIV, and cotinine. Safety assessments included moni- centration. At the time of conducting this study, no
toring and recording all observed and reported adverse sensitive bioanalytical method was available to mea-
events, blood chemistry, hematologic profile, urine sure plasma clopidogrel concentrations at a steady-
analysis, electrocardiogram (ECG) recordings, measure- state therapeutic dose (75 mg). Therefore, to assess
ments of vital signs, and physical examinations. the fluvastatin effect on clopidogrel, ADP-induced
Subjects between the ages of 19 and 45 years, in platelet aggregation and bleeding time were mea-
good health as determined by medical history, sured (see Pharmacodynamic Assessments).

614 • J Clin Pharmacol 2007;47:613-619

 CLOPIDOGREL HAS NO EFFECT ON FLUVASTATIN PHARMACOKINETICS

Fluvastatin Analysis blood samples were centrifuged at 100 g for 15 min-

utes to obtain platelet-rich plasma (PRP). The platelet
Serum concentrations of fluvastatin were measured count in PRP was adjusted to 250 000/mL. The
using high-performance liquid hromatography/ remaining sample was further centrifuged at 3000
tandem mass spectrometry (LC/MS/MS). A liquid rpm for 15 minutes to obtain platelet-poor plasma
chromatographic/tandem mass-spectrometric method (PPP), which was used as subject blank. Platelet
is described for the determination of fluvastatin in aggregation was induced by 5 µM ADP, and optical
human serum. Of the internal standard (450 ng/ density was measured using a Chrono-log Optical
mL of IS_XUO320 in 2.25% methanol), 50 µL was Aggregometer (Model 490-4DR with internal AGGRO/
added to 100-µL serum samples, which were thor- LINK interface and Windows software Version 5.1 or
oughly mixed and extracted using liquid partition- higher). The bleeding time was measured using the
ing with acetonitrile and saturated aqueous sodium Ivy method.14
chloride solution. The separation of analytes was
achieved on a WATERS XTerra RP18 column (3.0 × Pharmacokinetic Assessments
50 mm, 3.5 µm) with a mobile phase consisting of
0.1% acetic acid/methanol (35:65, v/v) at an iso- Pharmacokinetic parameters were calculated using
cratic flow rate of 0.5 mL/min. The sample injector serum fluvastatin concentrations by noncompartmen-
was then washed 3 times with mobile phase and 3 tal methods (WinNonlin Pro Version 4.1, Pharsight
times with acetonitrile after each sample injection. Corporation, Mountain View, Calif, USA). The phar-
Detection of analytes was accomplished using turbo macokinetic parameters included Cmax (maximum
ion spray (TIS) negative ionization (API4000) with concentration observed postdose), Ctrough (observed
the collision energy set at –20 V (ion spray voltage of predose concentration), tmax (time to Cmax), and AUCτ
–4500 V) while keeping the ceramic heater tempera- (area under the concentration-time curve [AUC] from
ture at 700°C. The parent compound has a selected 0 to the time of the dosing interval).
m/z ratio of 410.2 for the precursor and 348.2 for the
product. The internal standard has a selected m/z Statistical Analysis
ratio of 424.2 for the precursor and 362.0 for the
All subjects who completed the study with evalu-
product. Appropriate calibration standards and quality
able pharmacokinetic and pharmacodynamic mea-
control samples were used in the analytical proce-
surements were included in the data analysis.
dure. The analytical data were captured using WAT-
SON LIMS (Version 6.2.0.02) software. The limit of Pharmacokinetics
quantitation was 2.0 ng/mL. The assay was validated Fluvastatin pharmacokinetic parameters Cmax and
within a concentration range of 2 to 2000 ng/mL. AUCτ obtained on day 19 (fluvastatin + clopidogrel)
The accuracy and precision (percentage coefficient and day 9 (fluvastatin alone) were analyzed. Statistical
of variation [%CV]) for calibration, intraday, and analyses were performed on log-transformed para-
interday samples ranged from 96.0% to 112.0% and meter values, using SAS Version 8.2. Each parameter
1.1% to 17.2%, respectively. The stability of fluvas- was analyzed using a linear mixed-effect model, and
tatin was ensured for at least 4.5 months at –20°C, log-mean differences of treatment fluvastatin + clopi-
for at least 3 freeze-thaw cycles, and for at least 24 dogrel minus fluvastatin and corresponding 90%
hours at room temperature in human serum. confidence intervals (CIs) were calculated. These were
back-transformed and reported in the original scale.
Pharmacodynamic Assessments
Pharmacodynamics
The pharmacodynamic effect of clopidogrel in com- Percentage of ADP-induced platelet aggregation and
bination with fluvastatin was assessed by measur- bleeding time during treatment with fluvastatin +
ing inhibition of ADP-induced platelet aggregation clopidogrel (days 10 through 19) and end of study (day
and prolongation of template bleeding time. Blood 24) were compared with fluvastatin alone (day 9)
samples (5 mL/sample) were collected into tubes using a linear mixed-effect model. For bleeding time,
containing sodium citrate at 2 hours postdosing on the log-transformed data were used. All pharmacoki-
day 9 (prior to initiation of clopidogrel administra- netic and pharmacodynamic parameters during com-
tion); on days 10, 12, 14, 16, and 19 (fluvastatin and bined treatment with fluvastatin and clopidogrel were
clopidogrel); and on day 24 (end of study). The compared with fluvastatin alone (day 9).

DRUG INTERACTIONS 615

 AYALASOMAYAJULA ET AL

Table I Effects of Clopidogrel on Steady-State Pharmacokinetic Parameters of Fluvastatin

Fluvastatin Fluvastatin + Geometric 90% Confidence
Alone Clopidogrel Mean Ratios Interval (P Value)

Cmax, ng/mL 61.5 (47.5) 71.2 (31.6) 1.27 1.08-1.50 (.018)

AUCτ, ng·h/mL 233.2 (52.0) 222.6 (46.3) 0.98 0.85-1.13 (.824)
Ctrough, ng/mL 1.9 (180.3) 1.1 (170)
tmax, ha 2.00 (0.50-8.00) 2.50 (1.00-4.00)
t1/2, h 5.9 (96.3) 4.6 (91.1)
Data are expressed as mean (percentage coefficient of variation [%CV]), n = 24.
a. Data are median (minimum, maximum).

RESULTS in Figure 1. The derived pharmacokinetic parameters

are presented in Table I. Coadministration of fluvas-
Demographics, Safety, and Tolerability tatin with clopidogrel resulted in an increase in flu-
vastatin Cmax from 64.48 ng/mL (fluvastatin alone) to
A total of 30 healthy male volunteers who were aged 71.15 ng/mL (coadministration with clopidogrel).
33.3 ± 7 years, weighed 76.5 ± 10 kg, and had a height The geometric mean ratio for Cmax was 1.27 (P =
of 173.3 ± 7 cm were enrolled into the study. Of the .018). There was no effect of clopidogrel on fluvas-
enrolled subjects, 2 were Caucasian (6.7%), 4 were tatin AUCτ. The individual values for fluvastatin
African American (13.3%), and 24 (80%) were of other Cmax and AUCτ for subjects treated with fluvastatin
race/ethnicity (primarily Hispanic). No subjects of alone (day 9) and in combination with clopidogrel
Asian descent were enrolled into the study. (day 19) are shown in Figure 2. Clopidogrel had no
A total of 5 adverse events were reported by 4 effect on the median tmax of fluvastatin, suggesting no
subjects: nasal congestion, elevated creatine kinase influence of clopidogrel on fluvastatin absorption
(2 subjects), and constipation (reported twice by the rate. The apparent half-life for fluvastatin (extended-
same subject). All adverse events were considered release formulation) was similar when administered
mild in severity, and none compromised the safety alone or in combination with clopidogrel.
of participants. Four of 5 adverse events were con- The mean predose (Cmin) concentrations of fluvas-
sidered unrelated to the study drug, and 1 (elevated tatin prior to clopidogrel administration (days 7, 8, and
creatine kinase) was presumed to be related to the 9) and following clopidogrel administration (days 17,
study drug. Six subjects discontinued from the study. 18, and 19) are presented in Figure 3. Fluvastatin
One subject had an elevated creatine kinase value on plasma concentration reached steady state by day 7,
day 10, and another subject had an elevated creatine and clopidogrel had no effect on the steady-state levels.
kinase value on day 4 from the initiation of study
dosing. Both subjects indicated they had performed Effects of Clopidogrel on Platelet Function in the
strenuous exercise while participating in the study Presence of Fluvastatin
(protocol violation) and were discontinued. At the
end of study evaluations, creatine kinase values for The pharmacodynamic activity of clopidogrel in the
both subjects were within normal range. Two subjects presence of fluvastatin was measured as the change
withdrew their consent. One subject tested positive from baseline in ADP-induced platelet aggregation
in the drug test screen and was discontinued. One (Table II) and as prolongation of bleeding time (Table III).
subject did not follow up for the study. Pharmacoki- Administration of the loading dose of clopido-
netic and pharmacodynamic data obtained from 24 grel (day 10) decreased platelet aggregation by
subjects who completed all study procedures were 33.1% (range, 28%-38%) compared to baseline (P <
included in the data analysis. .001). Maintenance doses of clopidogrel resulted in
inhibition of platelet aggregation by 46.3% to 49.2%
Effects of Clopidogrel on the (days 12, 14, 16, and 19) compared to baseline (P <
Pharmacokinetics of Fluvastatin .001). Bleeding time increased with clopidogrel and
fluvastatin combination (days 10-16) compared to
The steady-state plasma concentration-time pro- fluvastatin alone (day 9). The observed increase in
files of fluvastatin, when administered alone or in bleeding time was statistically significant (P < .05)
combination with clopidogrel, were similar, as shown on day 16 (1.24-fold; range, 1.04-1.49) and day 19

616 • J Clin Pharmacol 2007;47:613-619

 CLOPIDOGREL HAS NO EFFECT ON FLUVASTATIN PHARMACOKINETICS

antagonist that inhibits CYP2C9 activity in vitro,13

90
raising the possibility of a potential drug-drug interac-
tion between fluvastatin and clopidogrel. Therefore,
this study examined the effect of clopidogrel on the
Concentration (ng/mL)

60
pharmacokinetics of fluvastatin and also determined
the extent of platelet inhibition (ADP-induced aggre-
gation) by clopidogrel in the presence of therapeutic
concentrations of fluvastatin.
30 The main finding in this study was that clopidogrel
had no significant effect on fluvastatin exposure
(AUC), although there was a small but statistically sig-
nificant increase in Cmax (Table I). The variability in
0 fluvastatin pharmacokinetics observed in this study is
0 4 8 12 16 20 24
Time (Hours) similar to that reported in earlier studies.16 The mag-
Fluvastatin alone Fluvastatin + Clopidogrel
nitude of effect of clopidogrel on fluvastatin Cmax (ratio
of geometric means 1.27) was similar to the estimated
coefficient of variation for Cmax (31.6%) and is not con-
Figure 1. Steady-state concentration-time profile following multiple- sidered to be clinically relevant. The absence of any
dose administrations of 80 mg fluvastatin (extended-release for- major effect of clopidogrel on fluvastatin pharmacoki-
mulation) with and without clopidogrel. Fluvastatin alone (solid netics in this study indicates that clopidogrel at thera-
square) and fluvastatin + clopidogrel (open circle). Data are mean
(SD), n = 24. peutic concentrations does not significantly inhibit
CYP 2C9 in vivo.
In vitro studies indicate that clopidogrel inhibits
(1.35-fold; range, 1.13-1.61) compared to day 9 CYP 2C9 activity by 53% at a concentration of 10
(baseline). The variability in bleeding time was very µM.13 Oral administration of high-dose clopidogrel
high, and as a result, the observed changes were not (600 mg), which is approximately 8-fold higher than
statistically significant on days 10, 12, and 14. the recommended therapeutic maintenance dose,
resulted in a mean Cmax of 38.0 ng/mL (0.9 µM).17
DISCUSSION The pharmacokinetics of clopidogrel are shown to
be dose linear between the 300- and 600-mg doses.18
Fluvastatin is a potent HMG-CoA reductase inhibitor Assuming linear pharmacokinetics for clopidogrel
that is predominantly metabolized by CYP2C9.15 between the 75- and 600-mg doses, the predicted
Clopidogrel is an irreversible ADP receptor (P2Y12) Cmax for clopidogrel at the 75-mg dose (~4.75 ng/mL)

120 600

80 400
AUCτ (ng.h/mL)
Cmax (ng/mL )

40 200

0 0
Fluvastatin alone Fluv asta tin + Clopidogrel Fluvastatin alone Fluvastatin + Clopidogrel

Figure 2. Individual Cmax and AUCτ values for fluvastatin following multiple-dose administration of 80 mg fluvastatin (extended-release
formulation) with and without clopidogrel.

DRUG INTERACTIONS 617

 AYALASOMAYAJULA ET AL

of clopidogrel (60 µM) are required to inhibit fluvas-

4
tatin metabolism by 50% in human liver micro-
somes (unpublished data).
The pharmacodynamic effects of clopidogrel in
3 the presence of fluvastatin were determined by mea-
Fluvastatin (ng/mL)

suring ADP (5 µM)–induced platelet aggregation and

bleeding time. Clopidogrel was observed to inhibit
2 platelet aggregation by 33% within 2 hours follow-
ing 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
1
effect of clopidogrel alone on ADP-induced platelet
aggregation, the magnitude of inhibition in the pres-
ence of therapeutic concentrations of fluvastatin was
0
similar to that reported for clopidogrel administered
Fluvastatin alone (Day 7, Day 8, and Day 9) alone using the same dosing regimen.12
Fluvastatin + Clopidogrel (Day 17, Day 18, and Day 19) Bleeding time also increased during combined
treatment with clopidogrel and fluvastatin. Despite
the large variability in bleeding time measurements
Figure 3. Mean predose concentrations (Ctrough) of fluvastatin and the relatively small number of subjects, observed
following multiple-dose administration of 80 mg fluvastatin
(extended-release formulation) with and without clopidogrel. increases were statistically significant on days 16
and 19 compared to day 9 (baseline), providing fur-
ther evidence for platelet inhibition.
Mach et al19 recently reported a small but statisti-
is 40-fold lower than CYP 2C9 inhibitory concentra- cally significant decrease in ADP-induced platelet
tions. We have confirmed that high concentrations aggregation when fluvastatin was coadministered

Table II Effect of Clopidogrel on ADP-Induced Platelet Aggregation in the Presence of Fluvastatin

Clopidogrel + Fluvastatin Treatment

Day 9 (Fluvastatin End of Study,

Day of Treatment Alone) Day 10 Day 12 Day 14 Day 16 Day 19 Day 24

Mean, % 76.9 43.6 30.0 29.5 27.5 30.3 62.9

(SD) (11.5) (19.4) (14.9) (15.8) (13.9) (15.1) (14.8)
P valuea <.001 <.001 <.001 <.001 <.001 <.001
Platelet aggregation (%) was measured in response to 5 µM adenosine diphosphate (ADP). Mean values are compared to fluvastatin alone (day 9), n = 24.
a. Based on a linear mixed model for repeated measurements with day/visit as fixed factor and compound symmetry covariance structure.

Table III Effect of Clopidogrel on Prolongation of Bleeding Time in the Presence of Fluvastatin
Clopidogrel + Fluvastatin Treatment

Day 9 (Fluvastatin End of Study,

Day of Treatment Alone) Day 10 Day 12 Day 14 Day 16 Day 19 Day 24

Geometric mean, min 5.9 6.2 6.7 6.7 7.4 8.0 5.5
Geometric mean ratios 1.05 1.13 1.14 1.24 1.35 0.93
(90% CI)a (0.88-1.25) (0.94-1.35) (0.95-1.36) (1.04-1.49) (1.13-1.61) (0.78-1.11)
P valuea .663 .266 .234 .043 .006 .498
Data are geometric means and geometric mean ratios (90% confidence interval [CI]) compared to fluvastatin alone (day 9), n = 24.
a. Based on a linear mixed model for repeated measurements with day/visit as fixed factor and compound symmetry covariance structure.

618 • J Clin Pharmacol 2007;47:613-619

 CLOPIDOGREL HAS NO EFFECT ON FLUVASTATIN PHARMACOKINETICS

with clopidogrel. The authors hypothesized that 5. Corsini A, Pazzucconi F, Arnaboldi L, et al. Direct effects of statins
clopidogrel increases fluvastatin concentrations by on the vascular wall. J Cardiovasc Pharmacol. 1998;31:773-778.
inhibiting CYP2C9 and that increased fluvastatin then 6. Liberopoulos EN, Daskalopoulou SS, Mikhailidis DP, Wierzbicki
AS, Elisaf MS. A review of the lipid-related effects of fluvastatin.
inhibits CYP3A4, resulting in decreased formation of
Curr Med Res Opin. 2005;21:231-244.
the active clopidogrel metabolite. In the absence of
7. Fischer V, Johanson L, Heitz F, et al. The 3-hydroxy-3-
any significant effect of clopidogrel on fluvastatin methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect
exposure, the hypothesized effect of fluvastatin on on human cytochrome P-450 and implications for metabolic drug
clopidogrel-mediated platelet aggregation cannot be interactions. Drug Metab Dispos. 1999;27:410-416.
explained. Although the interindividual variability 8. Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin
for the inhibition of platelet aggregation observed in after single and multiple doses in normal volunteers. J Clin
our study was comparable to previously published Pharmacol. 1992;32:630-638.
reports,12,20 the variability in the study by Mach et al19 9. Clarke TA, Waskell LA. The metabolism of clopidogrel is cat-
alyzed by human cytochrome P450 3A and is inhibited by ator-
was not reported, making direct comparison of results
vastatin. Drug Metab Disp. 2003;31:53-59.
difficult. In addition, the maximum observed Cmax
10. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces
value of fluvastatin in the presence of clopidogrel in the ability of clopidogrel to inhibit platelet aggregation: a new
this study (114.0 ng/mL, 0.26 µM) is well below the ki drug-drug interaction. Circulation. 2003;107:32-37.
value (94.3 µM) for CYP3A4 inhibition.21 Therefore, 11. Lau WC, Carville DG, Bates ER. Clinical significance of the
at clinical doses, it is highly unlikely that fluvastatin atorvastatin-clopidogrel drug-drug interaction. Circulation. 2004;
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One potential limitation of this study is that we 12. Savcic M, Hauert J, Bachmann F, Wyld PJ, Geudeline B,
did not evaluate the CYP 2C9 genotype. Cariou R. Clopidogrel loading dose regimens: kinetic profile of
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Hemost. 1999;25(suppl 2):15-19.
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13. Richter T, Murdter TE, Heinkele G, et al. Potent mechanism-
pharmacokinetics. Inhibition of ADP-induced platelet based inhibition of human CYP2B6 by clopidogrel and ticlopi-
aggregation by clopidogrel in combination with flu- dine. J Pharmacol Exp Ther. 2004;308:189-197.
vastatin was similar to that reported for clopidogrel 14. Mielke CH Jr, Kaneshiro MM, Maher IA, Weiner JM, Rapaport
alone. We conclude that fluvastatin and clopidogrel SI. The standardized normal Ivy bleeding time and its prolonga-
can be safely coadministered with no need for dosage tion by aspirin. Blood. 1969;34:204-215.
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tatin. Clin Pharmacokinet. 2001;40:263-281.
The authors sincerely acknowledge Chaitanya Joshi (SAS pro- 16. Barilla D, Prasad P, Hubert M, Gambhir-Shah K. Steady-state
grammer), Sarita Kannarath (SAS programmer), and Selene Leon, pharmacokinetics of fluvastatin in healthy subjects following a
PhD, for their contributions to the data management and statisti- new extended release fluvastatin tablet, Lescol® XL. Biopharm
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Financial disclosure: All authors are employees of Novartis clopidogrel after administration of a high loading dose. Thromb
Pharmaceuticals. Haemost. 2004;92:311-316.
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