Cardiomyopathies are a major cause of morbidity and death in domestic cats. In a large postmortem study,1 8.5% of cats had evidence of acquired myocardial disease. Arterial thromboembolism is a common complication of cardiomyopathy in cats, which causes death and profound morbidity. Previous studies1,2 have found that cardiac-origin thromboembolism may be a complication in 15% to 48% of cats with hypertrophic cardiomyopathy. Approximately 90% of cardiac thromboembolic events in cats are thromboemboli in the distal part of the aorta that bilaterally occlude the femoral and iliac arteries. A retrospective study3 of 100 cats with distal aortic thromboembolism found that the rate of survival past the initial episode of thromboembolism was only 37%.
Medications used to prevent arterial thromboembolism in cats with heart disease include several antiplatelet and anticoagulant drugs. Although antiplatelet medications such as clopidogrel and aspirin are often administered to prevent cardiac thromboembolism in cats, recurrence rates remain high.3,4,a Targeted warfarin administration has been used to treat and prevent thromboembolism in cats,3,5 but data regarding safety and efficacy are lacking. High variability in the definition of a safe and effective dose among individual cats and over time as well as the need for frequent coagulation testing to ensure appropriate administration make warfarin treatment risky and impractical in cats. Low-molecular-weight heparins may be effective for the prevention and treatment of thromboembolic disease in cats, but low-molecular-weight heparins must be administered by injection, which some owners may be unwilling to do, and current costs are prohibitive for long-term use in many situations.
Apixaban is a novel, orally administered factor Xa inhibitor approved by the US FDA in 2012 to reduce the risk of stroke or systemic embolism in human patients with nonvalvular atrial fibrillation. Apixaban is not approved for use in nonhuman species. Clinical trials of apixaban in humans with nonvalvular atrial fibrillation have revealed that the drug is superior to warfarin treatment for reducing the risk of stroke or systemic embolism.6 Apixaban treatment in humans can be safely used by means of standardized administration with no need for continuous monitoring of coagulation.7 Therefore, apixaban holds great potential for replacing targeted warfarin treatment as the standard of care for a variety of thrombotic conditions in humans.
In humans with chronic atrial fibrillation, stasis of blood flow within the left atrium is thought to be the primary mechanism responsible for thrombus formation.8,9 In human medicine, anticoagulation is preferred over antiplatelet treatment when stasis of blood flow is the primary thrombotic mechanism, as for deep vein thrombosis and atrial fibrillation.10–12 Stasis of flow within the left atrium is also proposed to be a primary mechanism of thrombus formation in cats with cardiomyopathy. Thus, it is not surprising that antiplatelet strategies have often been unsatisfying for preventing thromboembolic complications in cats with cardiomyopathy. In cats with heart disease, anticoagulant treatment is more likely than antiplatelet treatment to prevent intra-atrial thrombus formation and promote resolution of existing thrombi through endogenous fibrinolysis.
A critical need exists to identify an effective, safe, and cost-effective anticoagulant that can both prevent thrombus formation and treat existing thrombi in cats with cardiomyopathy. On the basis of existing data from human studies showing excellent efficacy of apixaban in patients with thromboembolism and deep vein thrombosis,6,13–15 apixaban would appear to be a strong candidate to fulfill this need. Apixaban pharmacokinetics, pharmacodynamics, and metabolism have been studied in multiple species7,16–19 but to our knowledge have not been evaluated in cats. The objective of the study reported here was to determine the pharmacokinetic and pharmacodynamic properties of apixaban after administration to healthy cats.
Materials and Methods
Animals
Five healthy purpose-bred university-owned domestic shorthair cats (2 spayed females and 3 neutered males) were used for the study. All cats were 1 year old. Body weight ranged from 3.4 to 5.6 kg (mean, 4.4 kg). All study protocols were approved by the Colorado State University Institutional Animal Care and Use Committee.
Preparation of apixaban
For oral administration, apixabanb was mixed with lactose powder and placed into individual capsules to provide a dose of 0.2 mg/kg. Capsules were refrigerated at 4°C until administration.
For IV administration, a solution of 1 mg of apixaban/mL was created. Apixabanb (10 mg) was mixed with 1 mL of dimethylacetamide, 2 mL of propylene glycol, and 7 mL of sterile water, as described elsewhere.16 The solution was filtered through a 0.22-μm filter and stored at 4°C until administration. Concentration of filtered drug was confirmed via high-performance liquid chromatography–tandem mass spectrometry.16,20
Drug administration and sample collection
Each cat was sedated with butorphanol (0.3 mg/kg, IV) to allow insertion of an indwelling catheter into a jugular vein. Butorphanol was then reversed with naloxone, and the cats were allowed to recover for at least 4 hours before apixaban administration. Each cat initially received a single dose of apixaban (0.2 mg/kg) administered orally. Blood samples (1.7 mL/sample) were collected via the indwelling catheter into sodium citrate tubes before (time 0) and 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes after drug administration. Patency of the catheter was maintained by intermittent flushes with saline (0.9% NaCl) solution that did not contain heparin. The indwelling catheter was removed after collection of the final blood sample. After a 1-week washout period, cats were again sedated with butorphanol. An indwelling catheter was inserted into a jugular vein, and another indwelling catheter was inserted in a cephalic vein. Naloxone was administered to reverse the butorphanol, and cats were allowed to recover for at least 4 hours before apixaban administration. A single dose (0.2 mg/kg) was administered IV as a bolus injection via the indwelling catheter in the cephalic vein. Blood samples were collected via the indwelling catheter in the jugular vein into sodium citrate tubes before (time 0) and 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes after drug administration.
For both portions of the study, blood samples were immediately placed on ice after collection and then centrifuged at 1,000 × g for 10 minutes. Plasma was separated and stored at −80°C until testing was performed.
Sample processing for pharmacokinetic analysis
The method for detection of apixaban was a modification of the methods used in previous studies16,20 conducted to evaluate apixaban concentrations in canine and human plasma. Apixaban concentrations in the feline plasma samples were measured via high-performance liquid chromatography–tandem mass spectrometry with concentrations calculated by use of linear regression analysis and extrapolation from a calibration curve generated by use of blank feline plasma fortified with increasing concentrations of apixaban. A 10-point calibration curve was generated with concentrations ranging from 1 to 1,000 ng/mL, with 6 quality control samples at each of 3 concentrations (low, 2.5 ng/mL; medium, 50 ng/mL; and high, 500 ng/mL). For analysis of the apixaban solution used for IV administration, a separate standard curve was generated by fortifying blank administration solution with apixaban (6 concentrations ranging from 100 to 2,000 ng/mL), with quality control samples at 500 and 1,500 ng/mL. Dilution standards were generated by fortifying blank administration solution with 1 mg of apixaban/mL and diluting the resulting mixture to a concentration of 1,000 ng/mL. The administration solution from the study was then diluted 1:1,000 and analyzed.
Plasma samples for high-performance liquid chromatography–tandem mass spectrometry analysis were prepared by protein precipitation with 300 μL of acetonitrile followed by mixing in a vortex device for 10 minutes. Samples were then centrifuged at 20,800 × g for 10 minutes, and the supernatant was diluted with 1 volume of water containing 1% formic acid. Samples were mixed in a vortex device and then added to glass autosampler vials; an aliquot (10 μL) was injected onto the liquid chromatography system. High-performance liquid chromatography was performed with a C18 (4.6 × 50-mm) columnc with a guard columnd and elution with water containing 1% formic acid and acetonitrile containing 0.1% formic acid in a gradient of linearly increasing concentrations of the acetonitrile–0.1% formic acid solution over 5 minutes. The mass spectrometer was used in multiple reaction monitoring mode with positive electrospray ionization with the transition monitored for apixaban at m/z 460.1→443.1.
Sample processing for pharmacodynamic analysis
Samples were prepared by use of a factor × kite in accordance with the manufacturer's instructions for the quantitative determination of factor × via its activation to factor Xa. This assay used Russell's viper venom to specifically activate factor × to factor Xa. Factor Xa (if not inhibited by apixaban) then cleaved a chromogenic substrate to cause a color change. Therefore, optical density of the reaction well was inversely proportional to the concentration of apixaban in plasma. The optical density values were considered to be the factor Xa activity. A standard curve was calculated by use of human plasmaf in serial 2-fold dilutions ranging from undiluted (defined as 100% activity) to a 1:128 dilution (defined as 0.782% activity). Logarithmic transformation of the percentage activity was then used to generate a linear equation with optical density. Plasma samples (50 μL) were added to wells of a 96-well plate, diluted 1:2 with the assay kit buffer, and warmed to 37°C for 3 to 4 minutes. Factor Xa chromogenic substrate was added, followed by Russell's viper venom and calcium dichloride (to recalcify the sample). Plates were then incubated for an additional 3 minutes to allow color development, and 20% acetic acid was added to stop the color change. Optical density of samples was measured with a plate readerg set at 405 nm. Duplicates of each sample were analyzed, and the mean value was used to determine activity on the basis of the equation for the standard curve.
Statistical analysis
Pharmacokinetic variables were expressed as mean ± SD. Pharmacokinetic analysis was first performed by use of noncompartmental analysis. Absolute bioavailability of apixaban in cats was estimated from the plasma area under the curve data after IV and oral administration. Compartmental analysis was performed by fitting of the appropriate compartmental model to the data collected by means of pharmacokinetic software.h Model fit was determined by examination of residuals and comparison of Akaike information criteria. Spearman correlation analysis was used to assess the association between plasma apixaban concentrations and optical density for the factor × assay.
Results
Animals
No apparent behavioral changes or other adverse effects were associated with the administration of the IV or PO formulations. After IV administration, mild hemolysis of plasma samples was evident, which resolved in all cats by the time of the 1,440-minute sample. Two blood samples from 1 cat during the oral-administration phase of the study were obtained by jugular venipuncture because the indwelling catheter became displaced. Two samples could not be obtained for 1 cat during the IV-administration phase of the study because of difficulty collecting blood from the indwelling catheter.
Pharmacodynamic effects of apixaban
Factor Xa activity changed as a function of time after IV or PO administration of a single dose of apixaban (Figure 1). After oral administration, peak reduction in factor Xa activity (corresponding to 38% factor × activity) was reached at 240 minutes. Factor Xa activity was significantly (P < 0.001) inversely correlated with the plasma apixaban concentration for IV (R = −0.944) and PO (R = −0.548) administration (Figure 2). There was no lag time between the reduction in factor Xa activity and plasma apixaban concentrations after IV or PO administration.
Mean ± SD apixaban concentration (circles and solid line) and factor Xa activity (squares and dashed line) in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. There was a 1-week washout period between oral and IV administrations; time of administration was designated as time 0. Factor Xa activity represents optical density of samples measured with a plate reader set at 405 nm (OD405). Notice that the scale for the apixaban concentration on the left y-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Mean ± SD apixaban concentration (circles and solid line) and factor Xa activity (squares and dashed line) in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. There was a 1-week washout period between oral and IV administrations; time of administration was designated as time 0. Factor Xa activity represents optical density of samples measured with a plate reader set at 405 nm (OD405). Notice that the scale for the apixaban concentration on the left y-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Mean ± SD apixaban concentration (circles and solid line) and factor Xa activity (squares and dashed line) in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. There was a 1-week washout period between oral and IV administrations; time of administration was designated as time 0. Factor Xa activity represents optical density of samples measured with a plate reader set at 405 nm (OD405). Notice that the scale for the apixaban concentration on the left y-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Correlation between apixaban concentration and factor Xa activity in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. The Spearman correlation coefficient was −0.548 after oral administration and −0.944 after IV administration.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Correlation between apixaban concentration and factor Xa activity in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. The Spearman correlation coefficient was −0.548 after oral administration and −0.944 after IV administration.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Correlation between apixaban concentration and factor Xa activity in plasma samples obtained after oral (A) and IV (B) administration of a single dose of apixaban (0.2 mg/kg) to 5 cats. The Spearman correlation coefficient was −0.548 after oral administration and −0.944 after IV administration.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Assay performance and stability of compounded apixaban
The calibration curve for feline plasma samples was linear from 1 to 1,000 ng/mL (r2, > 0.99), and accuracy and precision of all calibration points were within 15%. Accuracy and precision of quality control samples at low, medium, and high concentrations also were within 15%. Lower limit of quantitation was 1 ng/mL for plasma samples. Calibration curve for the administration solution was linear for concentrations between 100 and 2,000 ng/mL, and accuracy and precision of the quality control samples and the dilution standard were within 15%.
After conclusion of IV administration, a sample of the remaining IV formulation of apixaban was analyzed by use of high-performance liquid chromatography–tandem mass spectrometry. Concentration of the sample was as expected (1 mg/mL), which confirmed short-term stability of the IV formulation.
Pharmacokinetic effects of apixaban
Concentrations of apixaban in plasma over time after IV and PO administration were summarized (Figure 3). Plasma concentration–time data were analyzed by use of both compartmental and noncompartmental analysis. A compartmental model could not be adequately fit to the PO data; therefore, results of noncompartmental analysis for the PO data were summarized (Table 1). A 2-compartment model was found to be the best fit for the IV data, and pharmacokinetic parameters were summarized (Table 2).
Apixaban concentration in plasma samples obtained from each of 5 cats after oral (A) and IV (B) administration of a single dose (0.2 mg/kg). Each symbol represents results for 1 cat. Notice that the scale on the x-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Apixaban concentration in plasma samples obtained from each of 5 cats after oral (A) and IV (B) administration of a single dose (0.2 mg/kg). Each symbol represents results for 1 cat. Notice that the scale on the x-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Apixaban concentration in plasma samples obtained from each of 5 cats after oral (A) and IV (B) administration of a single dose (0.2 mg/kg). Each symbol represents results for 1 cat. Notice that the scale on the x-axis differs between panels.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.732
Mean ± SD values for noncompartmental analysis of pharmacokinetic parameters after oral administration of a single dose of apixaban (0.2 mg/kg) to 5 cats.
| Parameter | Mean ± SD |
|---|---|
| Cmax (ng/mL) | 74.2 ± 31.9 |
| AUC0–t (min•ng/mL) | 18,368 ± 8,934 |
| AUC0–∞ (min•ng/mL) | 19,968 ± 8,158 |
| AUCExtrap (%) | 10.0 ± 14.8 |
| AUMC0–t (min•min•ng/mL) | 4,702,377 ± 2,651,505 |
| AUMC0–∞ (min•min•ng/mL) | 6,183,664 ± 2,824,813 |
| Λz (min−1) | 0.005 ± 0.004 |
| t1/2 (min) | 198.5 ± 121.6 |
| Vz/F (mL) | 12,709 ± 6,692 |
| Cl/F (mL/min) | 48.6 ± 14.2 |
| MRT (min) | 308.2 ± 118.8 |
| MAT (min) | 231.2 ± 117.6 |
| Ka (min−1) | 0.006 ± 0.003 |
| F (%) | 85.5 ± 22.9 |
AUC0–∞ = Area under the plasma concentration–time curve extrapolated to infinity. AUC0–t = Area under the plasma concentration– time curve from time 0 until the last time point. AUCExtrap = Fraction of the area under the plasma concentration–time curve extrapolated beyond the last time point. AUMC0–∞ = Area under the first moment curve extrapolated to infinity. AUMC0–t = Area under the first moment curve from time 0 until the last time point. Cl/F = Apparent systemic clearance corrected for bioavailability. Cmax = Maximum plasma concentration. F = Oral bioavailability. Ka = Absorption rate constant. Λz = Slope of the terminal elimination phase. MAT = Mean absorbance time. MRT = Mean residence time. t1/2 = Half-life of the elimination phase. Vz/F = Apparent volume of distribution corrected for bioavailability.
Mean ± SD values for compartmental analysis of pharmacokinetic parameters after IV administration of a single dose of apixaban (0.2 mg/kg) to 5 cats.
| Parameter | Mean ± SD |
|---|---|
| Cmax (ng/mL) | 460.6 ± 54.6 |
| AUC0–∞ (min•ng/mL) | 21,839 ± 6,049 |
| AUMC (min•min•ng/mL) | 1,861,831 ± 763,401 |
| Cl (mL/min) | 42.8 ± 9.8 |
| ClD2 (mL/min) | 66.6 ± 50.1 |
| V1 (mL) | 1,970 ± 473 |
| V2 (mL) | 1,507 ± 800 |
| Vdss (mL) | 3,476 ± 885 |
| MRT (min) | 82.4 ± 17.4 |
| A (ng/mL) | 282.7 ± 54.9 |
| B (ng/mL) | 177.9 ± 39.8 |
| α (min−1) | 0.090 ± 0.057 |
| β (min−1) | 0.011 ± 0.002 |
| t1/2α (min) | 11.9 ± 8.7 |
| t1/2β (min) | 67.8 ± 13.5 |
| K10 (min−1) | 0.024 ± 0.011 |
| K10 t1/2 (min) | 33.8 ± 11.8 |
| K12 (min−1) | 0.038 ± 0.032 |
| K21 (min−1) | 0.039 ± 0.019 |
A = The y-axis intercept of the distribution phase. α = Slope of the distribution phase. AUMC = Area under the first moment curve. B = The y-axis intercept of the elimination phase. β = Slope of the elimination phase. Cl = Systemic clearance. ClD2 = Intercompartmental distributional clearance. K10 = Elimination rate constant from the central compartment. K12 = Transfer rate constant between the central compartment and the peripheral compartment. K21 = Transfer rate constant between the peripheral compartment and the central compartment. K10 t1/2 = Half-life of elimination from the central compartment. t1/2α = Half-life of the distribution phase. t1/2β = Half-life of the elimination phase. V1 = Volume of the central compartment. V2 = Volume of the second compartment. Vdss = Volume of distribution at steady state.
See Table 1 for remainder of key.
After oral administration to 3 cats, apixaban concentrations could not be detected in plasma beyond the 8-hour sampling time; therefore, the area under the curve from time 0 to infinity and half-life calculations were based on extrapolation from the 8-hour time point for these 3 cats.
Discussion
Analysis of results of the study reported here revealed promising properties of orally administered apixaban for use as an anticoagulant in cats. Apixaban was found to have a small volume of distribution and moderate clearance, and there was a significant correlation between plasma concentration and pharmacodynamic effect. Bioavailability of apixaban in cats (85.5%) was high and similar to that reported in chimpanzees (51%), rats (48%), and dogs (80%).16 In cats, the half-life of apixaban after IV and PO administration was similar to that previously reported in other species16; however, humans have a longer half-life of approximately 12 hours.7,19
With the single oral dose used in the present study, the effect of apixaban on factor Xa activity was negligible after 360 minutes as indicated by return to preadministration values at that time. If this finding were to hold true during repeated twice-daily administration, effective anticoagulation would not be maintained for a considerable portion of a day. This could provide a potential benefit of reducing the risk of hemorrhage by allowing periods for physiologic coagulation, but this could also limit the antithrombotic efficacy of apixaban at the evaluated dose. Higher doses or more frequent drug administration would increase the amount of time during which factor Xa is inhibited but could also increase the risk of hemorrhage. A study to evaluate administration of multiple doses of apixaban to cats is needed to address this issue. Currently, the target factor Xa activity for maximizing efficacy and simultaneously limiting risk of hemorrhage during apixaban treatment is not known with certainty because no such studies have been conducted in human or feline patients. However, factor Xa activity between 11% and 42% as measured by use of a chromogenic assay has been found to correlate to an international normalized ratio of 2.0 to 3.5 in humans receiving warfarin as an anticoagulant and is considered therapeutic.21
The 1-week washout period was chosen for the present study on the basis of data for rats, dogs, chimpanzees, and humans that indicated the longest half-life of apixaban in any of those species is 12 hours.16,20 For 99% of a drug to be eliminated from the body, a period equivalent to 7 half-lives is required. If the half-life in cats were to be as long as 12 hours, 3.5 days would allow for 99% of the drug to be eliminated. Therefore, it was estimated that the 1-week washout period would be adequate. Analysis of data for the cats revealed a half-life of 3.3 hours after oral administration. Thus, 99% of the apixaban would have been eliminated 23.1 hours after administration of the single oral dose, which would make any impact of oral administration on the IV results obtained 1 week later negligible.
No adverse effects were observed in the cats after IV or PO administration of apixaban. Mild hemolysis was evident in plasma obtained from all cats after administration of the IV formulation of apixaban; however, this hemolysis resolved by the time of the 1,440-minute sample. Hemolysis may have been caused by apixaban or by one of the carriers used in the formulation. However, hemolysis was not detected after oral administration of apixaban, despite comparable plasma concentrations. If the IV formulation were to be repeatedly administered, hemolysis could potentially have a negative impact on a patient. However, use of apixaban in cats with heart disease in clinical situations will likely involve solely oral administration (as is the case in humans for which the drug is approved only for oral administration). An IV formulation was developed for the present study to allow determination of oral bioavailability.
A limitation of the present study was the small number of cats, which reflected the intent of this study as an initial evaluation of apixaban, a drug with an unknown safety profile in cats. Despite the small number of cats, a significant relationship between plasma drug concentrations and factor Xa activity was found. A second limitation was that the study lacked randomization of the treatment order for the 2-period crossover design. The treatment protocol (oral administration followed by a 1-week washout period followed by IV administration) was used for several reasons. The IV formulation of apixaban could only be prepared as a single solution, and the stability of this formulation was not known. Therefore, the decision was made to administer the IV formulation to all cats during a single short period. In addition, the cats were only available for this study for a short period, which precluded use of a randomized, 2-period crossover design of the treatment order. A final limitation was that possible effects of the compounds in the IV formulation on coagulation variables were unknown, and these compounds may have contributed to the observed changes in factor Xa activity. However, similar changes in factor Xa activity were observed after oral administration of apixaban, which made it unlikely that there was an effect of the IV formulation.
Additional studies to evaluate single-dose pharmacokinetics and pharmacodynamics of apixaban in cats with samples collected between the 480- and 1,440-minute time points would be beneficial for obtaining a more accurate determination of half-life, bioavailability, and the area under the curve extrapolated to infinity. Studies of multidose administration of apixaban will also be beneficial because this medication will most likely be used as a long-term treatment for cats with high risk for thrombosis. Additional studies are also needed to evaluate the degree of apixaban protein binding in cats.
Analysis of the results of the present study indicated that apixaban was an effective inhibitor of factor Xa in cats, with no apparent serious adverse effects observed after 1-time administration. The role of apixaban for prevention and treatment of thromboembolic disease in cats should be considered further.
Acknowledgments
Supported by the Veterinary Pharmacology Research Foundation and by an American College of Veterinary Internal Medicine Cardiology Resident Grant.
The authors have no conflicts of interest.
Results of this study were presented in abstract form at the American College of Veterinary Internal Medicine Forum, Nashville, Tenn, June 2014.
Footnotes
Hogan D, Fox P, Jacob K, et al. Analysis of the feline arterial thromboembolism: clopidogrel vs. aspirin trial (FAT CAT) (abstr), in Proceedings. Annu Am Coll Vet Intern Med Forum 2013;177.
Eliquis, provided by Bristol-Myers Squibb, New York, NY.
C18 reverse-phase liquid chromatography column, Waters Corp, Milford, Mass.
C18 filter frit guard column, Phenomenex, Torrance, Calif.
DiaPharma factor × kit, DiaPharma Group Inc, West Chester, Ohio.
LAtrol abnormal control, American Diagnostica Inc, Stanford, Conn.
Multiskan spectrum, Thermo Scientific, Waltham, Mass.
WinNonlin software, Pharsight Corp, Mountain View, Calif.
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