multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of...

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects

This study examined the pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an investiga- tional inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in 50 healthy subjects by means of a randomized, double-blind parallel-group design. Volunteers received rising single and multiple doses of 0.5 to 80 mg/day atorvastatin (40 subjects) or placebo (10 subjects). The drug was administered once or twice daily for 14 days. Atorvastatin was well tolerated by healthy subjects. The most common adverse events reported after atorvastatin- headache and nausea- occurred as frequently after placebo. Atorvastatin peak concentration and area under the plasma concentration-time curve (AUC) values increased more than proportionally with atorvastatin dose after both single and multiple drug doses. The extent of atorvastatin absorption (AUC) was similar after once- or twice-daily drug administration. Steady-state drug concentrations were achieved by the third day of drug dosing. Mean elimination half-life values ranged from 11 to 24 hours. Atorvastatin accumulation was approximately 1.5- and 3.0-fold after once- and twice-daily administration, respectively. Atorvastatin produced dose-related reductions in total cholesterol and low-density lipoprotein cholesterol that were similar after once- and twice-daily drug administration. Reductions in mean total cholesterol and low-density lipoprotein cholesterol values ranged from 13% and 22% (2.5 mg/day) to 45% and 58% (80 mg/day), respectively (p zz 0.0013 in comparison with placebo and with baseline over this dose range). In summary, atorvastatin doses of up to 80 mg/day were well tolerated and had significant cholesterol-lowering effects. (Clin Pharmacol Ther 1996;60:687-95.)

Donald D. Cilla, Jr., PharmD, Lloyd R Whitfield, PhD, Donald M. Gibson, BS, Allen J. Sedman, MD, PhD, and Edward L. Posvar, MD Ann Arbor, Mich.

Atorvastatin is a synthetic inhibitor of 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase currently under clinical development. Pre- clinical data on the lipid-lowering ability of atorvastatin suggest that it is more potent than marketed inhibitors of HMG-CoA reductase. Atorvastatin inhibited HMG-CoA reductase in cultured rat hepatocytes by 50% at a concentra-

From the Department of Clinical Pharmacology and Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Phar- maceutical Research, Division of Warner-Lambert Company.

Received for publication Feb. 5, 1996; accepted July 11, 1996. Reprint requests: Allen J. Sedman, MD, PhD, Clinical Pharma-

cology Department, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105.

Copyright 0 1996 by Mosby-Year Book, Inc. 0009-9236/96/$5.00 + 0 13/l/76426

tion of 0.6 nmol/L, compared with 2.7 nmol/L for lovastatin and 5.5 nmol/L for pravastatin.’ Ator- vastatin also produced larger decreases than lovastatin in plasma triglycerides in rats and guinea pigs.2

In a previous clinical trial, atorvastatin was well tolerated by healthy subjects at single doses of up to 80 mg.” One subject who received a single 120 mg atorvastatin dose experienced mild transient restlessness, euphoria, and mental confusion that were considered to be dose-limiting side effects. The single-dose pharmacokinetic profile of atorvastatin equivalents in human plasma was nonlinear, and atorvastatin had a long half-life (t,,,; 14.7 to 57.6 hours). This study examined the safety, pharmacokinetic characteristics, and lipid- lowering ability of single and multiple doses of atorvastatin in healthy subjects.

687

688 Cilia et al. CLINICAL PHARMA COLOGY & THERAPEUTICS

DECEMBER 1996

MATERIAL AND METHODS Study design. Fifty healthy volunteers, 34 men and

16 women (median age, 35 years; age range, 19 to 55 years) participated in this study conducted at the Parke-Davis Community Research Clinic (CRC) in Ann Arbor, Mich., according to a protocol approved by the CRC Institutional Review Board. All subjects gave written informed consent before participating and were free of disease or medication that could interfere with interpretation of the study results. Potential subjects were excluded if they had a his- tory of adverse reactions to lipid-regulating agents or if they had recently donated blood or participated in other drug studies.

The study used a double-blind, parallel-group, rising single- and multiple-dose design in which subjects were assigned to five groups of 10 each; groups were enrolled separately in the absence of safety concerns at lower doses. In the first four groups, eight subjects received 10, 20, 40, or 80 mg atorvastatin daily (4 q.d., 4 b.i.d.) and two subjects received placebo. In a fifth group, added to character- ize the effects of lower drug doses, four subjects received 0.5 mg atorvastatin once daily, four subjects received 2.5 mg once daily, and two subjects received placebo. To determine whether single-dose pharmacokinetics were predictive of multiple-dose pharmacokinetics, subjects were given a single morning dose of atorvastatin on day 1 and then received 2 weeks of multiple-dose administration on days 8 to 21. A single dose was also given in the morning on day 22. Study medication was administered at 7 AM and 7 PM either 2 hours before or 2 hours after meals. Subjects receiving once-daily atorvastatin also received a placebo dose in the evening to maintain the study blind. Atorvastatin and placebo capsules were swallowed intact with 8 ounces of water.

Subjects fasted before all clinical laboratory measurements and continued to fast for 4 hours after the administration of the atorvastatin doses on days 1 and 22, except for 6 ounces of unsweetened fruit juice that was allowed after 2-hour blood draw. Physical examinations, electrocardiograms, vital sign measurements, fecal occult blood examinations, ophthalmologic examinations, and clinical laboratory measurements were performed at baseline and during the course of the study.

Pharmacokinetic methods. Blood samples (10 ml) were collected in glass tubes that contained heparin before each drug dose and at 1/2, 1, 2, 3, 4, 6, 8, 10, 12,24,36,48, and 72 hours after drug administration

on days 1 and 22, as well as before administration of the morning dose on days 11,15, and 18. Plasma was harvested from the samples and stored at -20” C until assayed.

Plasma samples were analyzed for atorvastatin- equivalent concentrations with use of a validated enzyme inhibition bioassay procedure.4 Atorvastatin was isolated from 0.25 ml human plasma by protein precipitation with acetonitrile/acetone (95:5). The supernatant (700 l.~l) was evaporated to dryness under nitrogen, and the residue was reconstituted with distilled water (50 ~1) and incubated with a buffer solution that contained [14C]HMG-CoA, cofactors, and HMG-CoA reductase from rat liver micro- somes. The [i4C]mevalonate produced was lacton- ized under acidic pH to yield [14C]mevalonolactone, which was separated from the reaction mixture with an AG l-X8 anion exchange column. The [14C]mevalonolactone measured by liquid scintillation spec- trometry was used to construct a standard curve. The curve was used to calculate the concentration of atorvastatin with use of a logitflog algorithm. Ator- vastatin metabolites or other endogenous materials in plasma capable of inhibiting HMG-CoA reductase were quantified. Atorvastatin concentration was therefore expressed in terms of atorvastatin equivalents.

The atorvastatin plasma assay was validated over a range of 0.36 ngEq/ml, the minimum quantifiable limit for a 0.25 ml sample, to 16.0 ngEq/ml. Assay precision, expressed as percent relative standard deviation (%RSD) of calibration standards and quality control samples during study sample analysis, ranged from 0.51% to 15.2%. Experimentally deter- mined concentrations of atorvastatin in quality control samples ranged from 97.0% to 114% of nominal values. [14C]Atorvastatin recovery from human plasma was 98.2%, 97.0%, and 97.6% at atorvastatin concentrations of 0.8, 3.2, and 9.6 ngEq/ml, respectively.

Atorvastatin equivalent pharmacokinetic parameters were obtained by noncompartmental analysis of plasma equivalent concentration-time data. Max- imum observed plasma atorvastatin equivalent concentration (C,,) and the time of C,, (tmax) were recorded on days 1 and 22. Area under the plasma concentration-time curve (AUC) was estimated with use of the linear trapezoidal method. AUC(O-24) on day 22 for the twice-a-day dose groups was calculated as two times AUC(O-12) values because half the dose was administered on that day. The elimination rate constant (X,) was esti-

CLINICAL PHARMACOLOGY &THERAPEUTICS VOLUME 60, NUMBER 6 Cilia et al. 689

Table I. Mean and %RSD atorvastatin pharmacokinetic parameters and drug accumulation ratios after administration of once daily doses for 14 days

AUC(O-24)

Dose G,,, fngEqW tmmar (W (ngEq . hrJm1) tl12 fk) R

hd * Mean %RSD Mean %RSD Mean %RSi? Mean %RSD Mean %RSD

2.5 1.95 41.5 5.3 61.0 25.2 56.9 11.0 47.7 2.3 78.7 10 7.41 16.1 2.0 0.0 77.6 23.2 24.1 60.2 1.6 30.0 20 14.9 12.1 2.3 41.7 164 23.7 19.5 49.5 1.6 21.9 40 66.8 38.2 2.5 23.2 618 31.6 20.7 22.2 1.3 28.5 80 252 52.8 2.0 70.0 1293 36.0 19.3 15.5 1.3 16.2

%RSD, Relative standard deviation; C,,, maximum observed plasma concentration; t,,,, time of C,,,; AUC(O-24), area under plasma concentration-time curve from time 0 to 24 hours after dosing; t,,,, elimination half-life; R, accumulation ratio calculated as day 22 AUC(O-24)iday 1 AUC(O-24).

*Atorvastatin concentrations after the 0.5 mg dose were below quantifiable levels.

Table II. Mean and %RSD atorvastatin pharmacokinetic parameters and drug accumulation ratios after administration of twice daily doses for 14 days

Dose G,,, fwW4

fmg) Mean %RSD t,, 04

Mean %RSD

AUC(O-24) (ngEq * hriml)

Mean %RSD tI12 W R

Mean %RSD Mean %RSD

5 3.85 16.6 3.8 111 38.1 14.4 11.3 14.5 3.0 13.0 10 11.5 25.3 5.0 40.0 102 24.5 16.0 40.1 3.2 8.4 20 24.3 36.8 1.8 55.6 186 29.1 17.3 7.3 3.2 26.6 40 115 99.8 2.3 42.7 775 39.7 13.9 16.9 3.7 29.7

AUC(O-12), Area under plasma concentration-time cmve from time 0 to 12 hours after dosing; R, accumulation ratio calculated as day 22 AUC(O-12)iday 1 AUC(O-12).

Table III. Mean percent change from baseline in total cholesterol, LDL-C, and triglycerides after 14 days of multiple-dose atorvastatin administration

Total cholesterol

Mean baseline Mean percent WI change from

hgfdU baseline (SD)

LDL-C Mean baseline Mean percent

(SD) change from fmgldl) baseline (SD)

Triglycedes Mean baseline Mean percent

(SD) change from hgidl) baseline (SD)

0.5 202 (58.4) -6.6 (6.6) 149 (50.8) -7.9 (7.6) 85.4 (47.6) -5.5 (27.0) 2.5 200 (46.7) -13.3 (5.6)* 138 (37.5) -22.4 (10.9)* 109 (50.3) 8.8 (39.8)

10 194 (27.6) -21.6 (8.3)* 130 (27.5) -30.5 (5.7)* 88.2 (23.2) -11.8 (17.7) 20 180 (31.8) -29.0 (9.0)* 123 (29.7) -39.2 (7.6)* 139 (80.5) -22.1 (23.7) 40 192 (39.1) -35.8 (6.1)* 134 (37.5) -46.7 (10.6)* 131 (69.9) - 13.6 (62.4) 80 173 (32.2) -44.8 (7.1)* 123 (31.2) -57.8 (6.1)* 104 (43.6) -24.7 (18.1)

Placebo 202 (35.3) -3.1 (7.4) 146 (27.8) - 1.7 (9.2) 114 (48.4) 2.1 (36.5)

LDL-C, Low-density lipoprotein cholesterol; SD, standard deviation. *p 5 0.0013 in comparison with placebo and with baseline.

mated as the absolute value of the slope of a least-squares linear regression of the natural log- arithm (In) of plasma atorvastatin equivalent concentration versus time during the terminal phase of the plasma concentration-time profile. Elimi- natron tIiz was calculated as 0.693/X,. Atorvastatin accumulation ratio values were calculated as AUC(O-24) on day 22 divided by AUC(O-24) on day 1 and AUC(O-12) on day 22 divided by

AUC(O-12) on day 1 after once- and twice-daily dosing, respectively.

Lipid-lowering e$ects. Plasma samples for lipid analysis were collected twice during screening and on days 1, 8, 11, 15, 18, 22, and 29. Total cholesterol was measured after hydrolysis of cholesterol esters and oxidation coupled with hydrogen peroxide production. Triglycerides were measured by hydrolysis to glycerol, followed by phosphoryla-

690 Cilia et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

DECEMBER 1996

500 : Total Cholesterol

+

+

3 2003 5 i &

1004 +

0 10 20 30 40 50 60 70 80

Atorvastatin Dose (mg/day)

0

10 20 30 40 50 60 70 80 Atorvastatin Dose (mg/day)

Fig. 1. Effect of atorvastatin dose on mean maximum observed plasma atorvastatin equivalent concentration (C,,) and area under the plasma concentration-time curve [AUC(O-24)] values after administration once (plus signs) or twice (open circles) daily for 2 weeks.

tion to glycerol-3-phosphate and conversion to dihydroxyacetone phosphate coupled with hydrogen peroxide production. Lipoproteins were separated by electrophoresis and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and very low- density lipoprotein cholesterol (VLDL-C) were measured by quantitative densitometry.

Lipid values reported by the Parke-Davis Pathol- ogy and Experimental Toxicology laboratory were compared with those of a CDC standardized laboratory (Pacific Biometrics, Seattle, Wash.) in a sep- arate study. Total cholesterol and triglyceride values

10 20 40

Atorvastatin Dose (me/day)

LDL Cholesterol

10

J

20 40 Atorvaatatin Dose @g/day)

80

Fig. 2. Effect of regimen and total daily atorvastatin dose on total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Values are least-squares mean percentage reduction from baseline after 14 days of atorvastatin.

from both laboratories were in good agreement; however, a small systematic bias in LDL-C values was discovered, and values were adjusted to corre- spond to the CDC laboratory values. Original and adjusted lipid values were analyzed for changes from baseline, and results with both sets of values were similar. Therefore the adjusted LDL-C values were used for data analyses and are presented here. High- density lipoprotein cholesterol and very low-density lipoprotein cholesterol values correlated poorly with those from the CDC certified laboratory and were therefore not evaluated further.

Lipid measurements were evaluated separately for the once- and twice-daily dosing regimens and were also pooled by total daily dose. Baseline lipid values were defined as the mean of the two values measured during screening and on day 1. Percent- age change from baseline was calculated for all lipid parameters, and mean percentage change from baseline was plotted against dose to describe the

CLINICAL PHARMA COLOGP & THERAPEUTICS VOLUME 60, NUMRER 6

Total Cholesterol Total Cholesterol

0 5 10

Days of Multiple Dosing

-50 ‘L 0 0.5 2.5 10 20 40 80


c

LDL Cholesterol

0 --

0.5 2.5 10 20 40 30


Fig. 3. Effect of total daily atorvastatin dose on total cholesterol and LDL cholesterol levels. Values are least- squares mean percentage reduction from baseline after 14 days of atorvastatin or placebo.

dose-response relationship. Mean percentage change from baseline was compared with placebo after atorvastatin administration with use of an ANOVA model.

RESULTS Safety. Atorvastatin was well tolerated by healthy

subjects. All subjects completed the trial, and no serious adverse events occurred. The nature and frequency of adverse events were not related to dose or regimen, and the percentage of subjects with side effects was similar after administration of atorvastatin (83%) and placebo (100%). Headache and nausea were the most common adverse events, reported by 58% and 15%, respectively, of subjects receiving atorvastatin and 80% and 20% of subjects receiving placebo. There were no drug-related, clinically significant changes in physical or ophthalmologic ex-

LDL Cholesterol

g ‘:J&p.,?---c-‘l-,

0 5 10 15

Day3 ol Mulliple Dosing

Fig. 4. Time course of atorvastatin-induced reductions in total cholesterol and LDL cholesterol for each dose. Val- ues are least-squares mean percentage reductions from baseline.

aminations, vital signs, electrocardiograms, or clinical laboratory tests.

Pharmacokinetics. After single atorvastatin doses on day 1, C,, and AUC(O-m) increased more than proportionally with dose over the 5 to 80 mg dose range. These results were similar to those observed in another study after single atorvastatin doses of 0.5 to 120 mg.3

Atorvastatin equivalent concentrations achieved steady state by the third day of multiple dosing. Mean atorvastatin C,,, and AUC (Tables I and II; Fig. 1) values increased more than proportionally with dose during multiple dosing. Extent of atorvastatin absorption was similar after administration of atorvastatin once and twice daily (Fig. 1). Mean elimination tl/, values ranged from 11.0 to 24.1 hours and were independent of dose. Overall atorvastatin accumulation was 1.6-fold and 3.3-fold after once- and twice-daily administration, respectively.

Single-dose pharmacokinetics were predictive of multiple-dose pharmacokinetics on the basis of sim- ilarities between AUC(O-w) values after single doses and AUC values over the dosing interval at steady state. Mean elimination t,,, values were also similar

692 Cilia et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

DECEMBER 1996

Total Cholesterol

aI g

OF---

d -10 j

E -20 $

g. -30;

! -40 :

6 -50 i

g -64 -70 i

0.5 2.5 10 20 40 80 Atorvastatin Dose (mg/day)

LDL Cholesterol 0: l

l

\ l

015 215 lb 20 4b 80 AtONSStStin Dose (mg/day)

Fig. 5. Relationship between total daily atorvastatin dose (solid circles, once a day; x symbol, twice a day) and percentage reduction in total cholesterol and LDL cholesterol values. The line represents the least-squares mean.

after single (16.0 hours) and multiple (17.2 hours) drug doses.

Z&id-lowering e$ects. Once and twice daily atorvastatin dosing regimens produced similar reductions in total cholesterol and LDL-C (Fig. 2). Results were therefore summarized by total daily dose rather than by dosing regimen. As shown in Table III and Fig. 3, atorvastatin decreased total cholesterol and LDL-C at all doses. Mean total cholesterol reductions ranged from 7% to 45%, and mean LDL-C reductions ranged from 8% to 58%.

Mean reductions in total cholesterol and LDL-C values after 14 days of treatment at doses of 2.5 mg or higher were statistically significant @ I 0.0013) compared with placebo. Pharmacody- namic steady state may not have been reached after atorvastatin was administered for 2 weeks, although a plateauing in the effect was evident at the end of this period (Fig. 4). Reductions in triglycerides were evident, although they were not highly dependent on drug dose (Table III).

Reductions in total cholesterol and LDL-C were highly correlated with total daily drug dose (Fig. 5). Response correlated better with dose than with pharmacokinetic measures of systemic drug exposure such as C,, and AUC values (Fig. 6).

DISCUSSION Atorvastatin was well tolerated at all doses and

had an adverse experience profile similar to that in subjects treated with placebo. The most common adverse effects reported after atorvastatin administration were headache and gastrointestinal com- plaints, both of which have been noted with other inhibitors of HMG-CoA reductase.5,6 Atorvastatin had no effect on liver enzymes. Transient mental status changes were observed in one subject receiving 120 mg atorvastatin in a previous clinical trial.3 However, similar symptoms were not evident in this study, despite the fact that C,, values after multiple oral doses of 80 mg every day (mean, 252 ngEq/ ml) were similar to the maximum concentration measured previously in the subject who experienced mental status changes (234 ngEq/ml).

Two subsequent clinical trials with atorvastatin in patients with hypercholesterolemia7 and hypertriglyceridemia’ at doses up to 80 mg a day for 6 and 4 weeks, respectively, confirmed that atorvastatin is well tolerated. Headache and mild elevations in ALT and AST, up to twice the upper limit of nor- mal, were reported in these studies.

The results of this study show that atorvastatin pharmacokinetics are nonlinear, as reflected by a greater than proportional increase in C,, and AUC with increasing single and multiple doses. This increase is consistent with saturable hepatic first-pass metabolism. However, this saturable process was not reflected in . . . ehmmation t,,, which was independent of dose. The t,, values were similar after single- and multiple-dose administration. Atorvastatin equivalent plasma concentrations achieved steady state by day 3 of multiple dosing, a result that is consistent with mean elimination t,/, values in the ll.O- to 24.1-hour range.

CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 60, NUMBER 6 Cilia et al. 693

-10

-20

-30

40

-50

-80

-70 ! I 1 10 100

Dose (mg)

0

-10 1 l

-20 .’

30 a

b 40 l l

-50

40 1

l

r2=0.591

l

l

b

-70 ! 1 10 100 1000

Cmax (ng eq/mL)

0

-10

-20

-30

40

-50

-80

-70

1 r*=0.578

C

10 100 1000

AUC (ng eq*hr/mL)

Fig. 6. Correlation between atorvastatin-induced reductions in LDL cholesterol and total daily atorvastatin dose (A), C,,, values (B), and AUC values (C).

Mean atorvastatin C,, and tmax values of 66.8 higher than values for lovastatin (284.6 ngEq * hr/ml) @q/ml and 2.5 hours in this study were similar to and pravastatin (189.3 ngEq * hr/ml), and mean ator- those observed for lovastatin (69.6 ngEq/ml and 2.3 vastatin elimination t,,* (20.7 hours) was sevenfold hours) and pravastatin (65.7 ngEq/ml and 1.0 hour) in longer that the t,,z values of lovastatin (2.8 hours) and a multiple-dose two-way crossover study in healthy pravastatin (2.7 hours). The basis for the prolonged t,/, subjects that used doses and analytical methods similar of atorvastatin has not been established. However, to those in this study.’ However, mean atorvastatin subsequent studies have shown that the majority of AUC (618 ngEq * hr/ml) was approximately threefold circulating inhibitory activity in plasma is accounted

694 Cilla et al.

for by active metabolites and that these active metabolites are long-lived.*

Atorvastatin produced statistically significant reductions in total cholesterol and LDLC at daily doses of 2.5 mg and above. Atorvastatin at 2.5 mglday produced mean reductions in total cholesterol and LDLC of 13% and 22%, respectively. Total cholesterol and LDL-C reductions of 45% and 58% were observed after treatment with 80 mg/day. Lipid response-time curves suggest that steady-state lipid concentrations may not have been reached after 2 weeks of atorvastatin administration, and slightly greater decreases may be possible with extended therapy.

Dose-response data for marketed inhibitors of HMG-CoA reductase suggest that lipid-lowering effects in healthy subjects are predictive of response in patients. The dose-response curves for lovastatin in healthy subjects” and in patients with familial and nonfamilial hypercholesterolemialr are similar. Dose-response curves for pravastatin in healthy sub- jectP underestimated dose response in patients” but accurately predicted doses at which maximum pharmacologic effect occurred. Based on the cholesterol reductions observed in this 2-week study in healthy subjects, a daily dose range of 2.5 to 80 mg was selected for a 6-week study in patients with primary hypercholesterolemia.7 Reductions in total cholesterol and LDL-C with atorvastatin were 17% and 25% at 2.5 mg, 22% and 29% at 5 mg, 30% and 41% at 10 mg, 35% and 44% at 20 mg, 38% and 50% at 40 mg, and 46% and 61% at 80 mg, respectively. Thus the dose-response curve for atorvastatin in healthy subjects was predictive of the dose-response curve for atorvastatin in patients with hypercholesterolemia.

The effect of atorvastatin on plasma LDL-C at the end of the 2-week dosing period correlated better with dose than with measures of systemic exposure, that is, C,, and AUC. This lack of correlation between measures of systemic exposure and lipid effects was also seen in patients with heterozygous familial hypercholesterolemia receiving fluvastatin: Their LDL-C reductions ranged from lo%-19% to 33%-39%, despite the fact that the AUC values for all patients were similar. l3 Thus atorvastatin dose is likely to be a better index of hepatic exposure than plasma C,, or AUC values because atorvastatin is active primarily in the liver. This is supported by an autoradiography study in rats that showed 14C-

*Yang BB, Smithers JA, Olson SC, Stem RH. Unpublished data on file at Parke-Davis Pharmaceutical Research; RR 744- 00247, March 28, 1996.

CLINICAL PHARMACOLOGY &THERAPEUTICS DECEMBER 1996

atorvastatin equivalents accumulated in liver and remained there longer than in plasma.? However, although these observations together suggest that the efficacy of atorvastatin is better predicted by drug dose than by C,, or AUC, further study is needed to assess the relationship between potential side effects and systemic exposure.

In summary, the good safety profile and the graded pharmacologic response shown by atorvastatin over a dose range of 2.5 to 80 mg suggest the drug may be a new single agent therapy for treatment of a range of patients with mild to severe hypercholesterolemia. Subsequent clinical studies in patients will further define the usefulness of atorvastatin in the treatment of lipid disorders.

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2.

3.

4.

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Shaw MK, Sliskovic DR, Roth B, Newton R, Krause BR. Hep-G2 cells resemble fibroblasts but not primary rat hepatocytes in their response to inhibition of HMG- COA reductase [abstract]. FASEB J 1990;4:A533. Krause BR, Bousley R, Kieft K, Stanfield R, Newton RS. Atorvastatin is superior to lovastatin for lowering plasma triglycerides in experimental animals [abstract]. FASEB J 1993;7:A567. Posvar EL, Radulovic LL, Cilla DD, Whitfield LR, Sedman AJ. Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG- CoA reductase, in healthy subjects. J Clin Pharmacol 1996;36:728-31. Shum YY, Huang H, Walter G, Black AE, Sekerke CS, Homan R, et al. Development and validation of an enzyme inhibition assay for quantitation of CI-981 in human plasma [abstract]. Pharm Res 1993; 1o(suppl):s-415. Levy RI, Troendle AJ, Fattu JM. A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation 1993;87[suppl III]:4553. Davignon J, Montigny M, Dufour R. HMG-CoA reductase inhibitors: A look back and a look ahead. Can J Cardiol 1992;8:843-64. Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG- CoA reductase inhibitor. Arterioscler Thromb Vast Biol 1995;15:678-82. Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn SL, Weiss SR, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor,

TMcNally W, Dehart P, Shum Y, Chang T. Unpublished data on file at Parke-Davis Pharmaceutical Research; RR 764-01869, August 4, 1992.

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atorvastatin, in patients with hypertriglyceridemia. JAMA 1996;275:128-33,

9. Pan HY, De Vault AR, Wang-Iverson D, Ivashkiv E, Swanson BN, Sugerman AA. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J Clin Pharmacol 1990;30:1128-35.

10. Tobert JA, Bell GD, Birtwell J, James I, Kukovetz WR, Pryor JS, et al. Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl- coenzyme A reductase, in healthy volunteers. J Clin Invest 1982;69:913-9.

11. Mehta M, editor. Physicians desk reference on CD- ROM. Montvale NJ: Medical Economics Data Pro- duction Company, 1993.

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12. Pan HY, Funke PT, Willard DA, McKinstry DN. Pharmacokinetics, pharmacodynamics and safety of pravastatin sodium, a potent inhibitor of HMG-CoA reductase, in healthy volunteers. In: LaRosa JC, editor. New advances in the control of lipid metabolism: focus on pravastatin. Royal Society of Medicine Ser- vices international congress and symposium series No. 162, 1989:9-22.

13. Leitersdorf E, Eisenberg S, Eliav 0, Friedlander Y, Berkman N, Dann EJ, et al. Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia. Circulation 1993;87[suppl III]:3544.

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