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PHARMACOKINETICS |
From Abbott Laboratories, Abbott Park, Illinois.
Address for reprints: Rajendra S. Pradhan, PhD, Department R4PK, Building AP13 A-3, 100 Abbott Park Road, Abbott Park, IL 60064.
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ABSTRACT |
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Key Words: ABT-578 • pharmacokinetics • safety • multiple dose
ABT-578, a sirolimus analog, is anticipated to have comparable activity in reducing neointimal hyperplasia following coronary stenting and is currently in phase III of drug device development for use in drug-eluting stents. ABT-578 differs from sirolimus by substitution of a tetrazole ring in the 42-position (Figure 1). The mechanism of action of ABT-578 is similar to sirolimus. In smooth muscle cells, it binds to the intracellular protein FKBP-12, which then combines with and inhibits the protein kinase mammalian target of sirolimus (mTOR) and blocks progression of the cell cycle.8,9 ABT-578 is a cytostatic compound that does not cause cell death but cell cycle arrest in the S-phase. Preclinical in vitro experiments have shown that ABT-578 has similar potency as sirolimus in inhibiting human coronary artery smooth muscle cell and endothelial cell proliferation.10,11 In vivo studies in the swine model have shown a significant reduction in neointimal formation in the coronary artery when ABT-578 was delivered via stents.12
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
Subjects signed a written informed consent form prior to participation in the study. Subjects underwent a screening visit within 28 days prior to the study drug administration and were considered eligible for the study if they were men or women between 18 and 60 years of age; were in general good health based on medical history, physical examination, vital signs, and laboratory profile (serum electrolytes, blood urea nitrogen, serum creatinine, liver function, urine analysis, and complete blood count with differential); and were within 15% of the body weight ideal for sex, height, and body frame. Women were of nonchildbearing potential. Subjects were excluded from the study if they had a history of major medical illness, had abnormal results in electrocardiogram (ECG) or laboratory tests (including HIV and hepatitis tests), had consumed alcohol within 72 hours from the start of the study, were tobacco users within 6 months preceding study drug administration, had taken (or were required to regularly take) over-the-counter medications within 2 weeks of dosing, had a history of allergies to any medication, had a recent (6-month) history of drug or alcohol abuse, used known inhibitors (eg, ketoconazole, grapefruit juice) or inducers (eg, carbamazepine) of cytochrome P450 3A (CYP3A) within 1 month prior to study drug administration, received any drug by injection within 30 days prior to study drug administration, had donated or lost 550 mL or more blood volume (including plasmapheresis) or received a transfusion of any blood product within 8 weeks prior to study drug administration, had received any investigational drug within 6 weeks or within 10 times the respective elimination half-life (whichever was longer) prior to study drug administration, or had previously received ABT-578 or was considered by the investigator, for any reason, to be an unsuitable candidate for receiving ABT-578.
Drug Administration
Subjects received, under fasting conditions, a single 60-minute daily (qd) intravenous infusion of 200, 400, or 800 µg of ABT-578 or a matching intravenous infusion of placebo (vehicle only) for groups I, II and III, respectively, at approximately 8 AM on study days 1 through 14. ABT-578 and placebo were supplied by Investigational Drug Services at Abbott Laboratories (200 µg/mL in 40% propylene glycol, 10% ethanol) and were protected from light until the time of administration. The drug was administered via a syringe pump connected to a y-site device, which also infused 125 to 150 mL of 5% aqueous dextrose solution (D5W) over 60 minutes. The groups were dosed sequentially, with at least 7 days separating the last dose of the previous group and the first dose of the next group, during which time safety data from the previous group were reviewed. Dose escalation continued if there were no safety concerns in the subjects at the previous dose level.
Confinement and Diet
Subjects were confined to the study site and supervised for approximately 23 days. Confinement in each period began on study day –2 and ended on study day 21. Subjects returned to the study site for the final evaluation on study day 44. Breakfast was consumed after drug administration, except on days for pharmacokinetic sampling (days 1 and 14); lunch was consumed at approximately 1200 hours, dinner at approximately 1900 hours, and a snack at approximately 2130 hours. The meals consumed on all days were standardized for calorie and composition and were the same for all subjects. The sequence of starting meals on study days 1 through 14 was maintained such that the time intervals between dosing and meals were essentially the same for all subjects. Subjects did not consume grapefruit, grapefruit products, caffeine, or alcohol during confinement.
Sample Collection and Analysis
We collected 5-mL blood samples in potassium EDTA-containing tubes to evaluate ABT-578 concentrations prior to dosing (0 hour) and at 0.25, 0.5, 1.0, 1 hour 5 minutes, 1.25, 1.5, 2, 3, 4, 8, 12, 18, and 24 hours after starting infusion on study days 1 and 14. Additional samples were collected at 36, 48, 72, 96, 120, 144, and 168 hours after starting infusion on study day 14 and prior to dosing on study days 10, 11, 12, and 13. Whole-blood samples were frozen within 30 minutes after collection and remained frozen at –70°C until analyzed at Abbott Laboratories. Blood concentrations of ABT-578 were determined using a validated liquid/liquid extraction high-performance liquid chromatography (HPLC) tandem mass-spectrometric method (LC/MS/MS).13 Sirolimus was used as an internal standard. Samples were analyzed by subject such that all subject samples were analyzed in the same analytical run. The lower limit of quantification (LLOQ) of ABT-578 was established at 0.20 ng/mL using a 0.3-mL blood sample. In-study quality control (QC) samples, supplemented with concentrations of 0.50, 1.50, 7.49, 34.95, and 159.75 ng/mL of ABT-578, were analyzed with the unknowns. Coefficient of variation values for the accepted data were equal to or less than 11.8%; the mean analytical recoveries ranged from 0.6% to 2.8% of their theoretical values.
Urine was collected in containers without preservatives over the following intervals: 0 to 6, 6 to 12, 12 to 18, and 18 to 24 hours after starting the infusion on study days 1 and 14. Urine was also collected for 24-hour intervals on study days 16, 18, and 20. The volume of urine over a collection interval was recorded. Then, 5-mL urine samples from each collection interval were stored frozen at –70°C until analyzed at Abbott Laboratories. Urine concentrations of ABT-578 were determined using a modified validated liquid/liquid extraction HPLC tandem mass-spectrometric method (LC/MS/MS).13 Sirolimus was used as an internal standard. Samples were analyzed by subject such that all subject samples were analyzed in the same analytical run. The LLOQ of ABT-578 was established at 0.50 ng/mL using a 0.3-mL urine sample. In-study QC samples, supplemented with concentrations of 1.26, 10.07, 100.72, and 161.16 ng/mL of ABT-578, were analyzed with the unknowns. Coefficient of variation values for the accepted data were equal to or less than 12.4%; the mean analytical recoveries ranged from –11.6% to 10.6% of their theoretical values.
Immunological Monitoring
To determine the immunological activity of ABT-578, a mitogen-stimulated lymphocyte proliferation assay was performed (TNO Prevention and Health, Leiden, the Netherlands). On study days –1, 3, 7, 15, 21, and 44, 10-mL blood samples in EDTA tubes were collected to determine the ability of ABT-578 to inhibit mitogen-stimulated lymphocyte proliferation. Peripheral blood mononuclear cells (PBMCs) obtained from the blood were separated by density centrifugation. Following washing, the PBMC fraction was resuspended in culture medium, and the cell number in each sample was enumerated by using a Coulter MAXM. Cells were then cultured in a humidified CO2 incubator at 37°C in the absence or presence of phytohemagglutinin at suboptimal (0.25 µg/mL) and optimal concentrations (1.0 µg/mL) of mitogen for 90 hours. All cultures were performed 6-fold in flat-bottom microtiter plates in the absence of any added ABT-578. 3H-methyl-thymidine was added to each of the cultures the final for 6 hours of incubation, and all reactions were terminated by placing the plates at –20°C. At a later time point, plates were thawed and harvested. This procedure resulted in lysis of the cells, followed by binding of the radioactive DNA to filters. Radioactivity on the filters was measured using ß-counters. Mitogen-stimulated response of cryopreserved PBMCs from 2 healthy donors was used as a positive control in each experiment. The extent of proliferation was expressed as the stimulation index, which was based on the incorporation of 3H-methyl-thymidine into the DNA compared with the unstimulated cells. The test results were accepted when at least 1 of the 2 included control cell batches showed a stimulation index of at least 10 in the presence of 1 µg/mL phytohemagglutinin.
Safety Monitoring
All observed or volunteered adverse events were recorded after administration of each dose with regard to their time of onset, severity, duration, and possible relationship to the study drug. Vital signs, physical examinations, ECG recording, injection site inspection, hematology, leukocyte subsets, IgG, and clinical chemistry were monitored throughout the study.
Pharmacokinetic Analysis
Pharmacokinetic analysis was performed on the ABT-578 blood concentration-time data for individual subjects. Estimates of pharmacokinetic parameters were obtained by compartmental methods using WinNonlin-Pro, Version 4.0 (Pharsight Corporation, Cary, NC). Data from the first dose on study day 1, the last dose on study day 14, and the trough concentrations on study days 10, 11, 12, and 13 were simultaneously modeled for each individual subject. One-, 2-, and 3-compartment models were evaluated to determine the best-fit model. Various weighting schemes, including a weight of 1, 1/y (y is drug concentration), 1/y2, 1/y^ (y^ is predicted concentration), and 1/y^2, were applied. Goodness of fit was assessed on visual inspection of plots of observed versus predicted concentrations, residual distribution versus time, and observed and predicted concentrations versus time along with coefficient of variation of parameters (%CV), weighted sum of squares of residuals (WSSR), the Akaike information criterion (AIC), and the Schwartz criterion (SC). Generally, the model with the lowest AIC and the optimal diagnostic plots, %CV with lower values for WSSR and SC, was chosen as the best-fit model. The primary parameters estimated for each subject from the model were volume of the central compartment (V1) and terminal elimination rate constant (
). Concentrations below the LLOQ (0.2 ng/mL) were not included in the calculation of . In addition, secondary parameters estimated were clearance (CL), volume of distribution at steady state (Vss), half-life (t1/2), maximum concentration (Cmax) and time of maximum concentration (tmax), and area under the blood concentration versus time curve for day 14 (AUC
). Corresponding dose-normalized Cmax and AUC were also estimated. In addition, dose and time linearity over the studied doses were evaluated.
The optimal model for each individual subject was used to predict the individual's concentration-time profile over a 14-day period to estimate the chronic exposure over the study duration, that is, Cmax and all-day AUC0-
(area under the predicted blood concentration-time profile from time 0 to infinity, taking into account all 14 doses in the study). The AUCs were calculated using the trapezoidal rule.
Statistical Analysis
To assess dose proportionality for the study day 14 dose, an analysis of covariance (ANCOVA) for the logarithm of dose-normalized Cmax, dose-normalized AUC, and terminal elimination rate constant was performed with SAS, Version 6.12 (SAS Institute, Cary, NC). The center and the dose were factors, and body weight was a covariate. The primary test was a comparison of the lowest and the highest doses within the framework of ANCOVA. To address the question of whether steady state was reached, a repeated-measures analysis, with center, dose level, and study day as factors, was performed on the dose-normalized predose concentrations of study days 10 to 14.
For the lymphocyte proliferation stimulation index, an ANCOVA was performed on the change from baseline (study day –1) to the measurement on study day 15. The ANCOVA had effects for site, dose level (with placebo considered a 0-µg dose), and the interaction of site and dose level and had the baseline value as a covariate. The significance level of all statistical tests was .05.
The sample size of the study (16 subjects on ABT-578 and 8 subjects on placebo for each dose level) was able to detect a difference of about 1 standard deviation (SD) between the 800-µg group and the placebo group with 90% power.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Results of the compartmental analysis of the blood concentration-time data show that generally, the data for all subjects are described adequately by a 3-compartment open model with first-order elimination and with a weight of 1/y^ (1/y^ stands for inverse of the predicted concentration).
The mean ± SD of Cmax and AUC for day 14 versus dose is presented in Figure 3. The mean ± SD Cmax of ABT-578 on day 14 for the 200-, 400-, and 800-µg qd dose groups was 11.21 ± 1.31, 21.37 ± 2.42, and 38.68 ± 6.43 ng/mL, respectively. The dose-normalized Cmax of ABT-578 for the 14-day regimen for the 200-, 400-, and 800-µg qd dose groups was 0.056 ± 0.006, 0.053 ± 0.006, and 0.048 ± 0.008 ng/mL/µg, respectively. The dose-normalized Cmax of the subjects at the 800-µgdoselevel was slightly but statistically lower than that of those at the 400- and 200-µgdoselevels(P = .0056 and .0015, respectively), which would indicate that increasing the dose would result in a statistically significantly smaller than expected increase in Cmax if the Cmax was dose proportional. Nevertheless, a difference of 0.008 ng/mL, which was about 14% of the dose-normalized Cmax of the subjects at the 200-µg dose level, in this parallel group design study is considered not to be of clinical significance.
The mean ± SD AUC of ABT-578 on day 14 for the 200-, 400-, and 800-µg qd dose groups was 48.99 ± 6.24, 104.62 ± 19.09, and 179.51 ± 17.40 ng·h/mL, respectively. The dose-normalized AUCT of ABT-578 on day 14 for the 200-, 400-, and 800-µg qd dose groups was 0.245 ± 0.031, 0.260 ± 0.047, and 0.224 ± 0.022 ng·h/mL/µg, respectively. Although the dose-normalized AUC was significantly different between the 400- and 800-µgdosegroups(P = .0055), the trend over the studied dose range was not statistically significant as the highest value for the dose-normalized AUC was observed for the 400-µg dose group. There was no statistical difference in the dose-normalized AUC between the highest and the lowest dose groups (P = .172)
Over the studied dose regimens, the mean CL of ABT-578 ranged from 4.0 to 4.6 L/h. The mean volume of the central compartment (V1) and the volume of distribution at steady state (Vss) ranged from 11.3 to 13.1 L and 92.5 to 118.0 L, respectively. The terminal elimination rate constant () of ABT-578 ranged from 0.022 to 0.028 h–1, and the corresponding harmonic mean of the half-life (t1/2) of ABT-578 ranged from 24.7 to 31.0 hours over the studied dose regimens.
Dose linearity was inferred for ABT-578 over the studied dose regimens because there was no bias in the observed versus predicted diagnostic plots, the ranges of the compartmental pharmacokinetic parameters were very narrow, and no meaningful trend in the secondary parameters was observed.
To evaluate the time invariance in ABT-578 pharmacokinetics, the average concentration data following dosing on days 1 and 14, as well as the average trough concentrations on days 10, 11, 12, 13, and 14 for each dose regimen, were fitted using a 3-compartment model. The plot for the mean observed and predicted blood concentrations versus time for the 800-µg qd dose group is presented in Figure 4 as an example. It illustrates that the model correctly describes the data on day 1 as well as day 14 and in between. The excellent fit of the observed ABT-578 concentration-time data over days 1 through 14 by a 3-compartment model assumes linear kinetics. This indicates that ABT-578 exhibits time-invariant clearance.
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The mean ± SD of trough samples for ABT-578 for each dose group on days 10, 11, 12, 13, and 14 are presented in Table II. At each dose level, day 10, 11, 12, and 13 trough concentrations were not statistically different from day 14 trough concentrations (P = .3856, .5387, .1144, and .3848, respectively). Therefore, ABT-578 concentrations were at steady state on or before day 10, the day on which the first trough sample was measured.
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The individual parameters from the compartmental analysis were used to simulate individual ABT-578 blood concentration-time profiles for qd dosing over the 14 days. Cmax and AUC from time 0 to infinity (all-day AUC0-) for the entire dosing and postdosing intervals were also calculated from the predicted concentrations. These parameters described the total exposure of ABT-578 following 14 qd doses. The all-day AUC0-last was calculated using the trapezoidal rule. The extrapolated AUCext was calculated by dividing the last measurable concentration by . The all-day AUC0- was the sum of all-day AUC0-last and AUCext. The medians of the Cmax for the 200-, 400-, and 800-µg qd dose groups were 11.4, 22.1, and 38.9 ng/mL, respectively. The corresponding all-day AUC0- was 677, 1438, and 2395 ng·h/mL, respectively.
The fraction of the ABT-578 dose eliminated in the urine was calculated for the 800-µg qd dose group. On average, approximately 0.1% of unchanged ABT-578 was recovered in the urine within a 24-hour period on days 1 and 14. Because very low concentrations of ABT-578 were recovered from the urine at the highest dose, samples from the lower dose groups were not analyzed. Renal excretion is not considered to be a major elimination pathway for ABT-578.
Immunological Markers
To assess a change in the immunological status of subjects administered ABT-578, percentage change in the stimulation index from baseline over time was calculated. Decreases were observed in the stimulation indices in the ABT-578 400-µg dose group on days 3, 7, and 15. Results of the ANCOVA for changes in lymphocyte proliferation activity from baseline to postdose measurements revealed statistically significant differences between the 400-µg ABT-578 dosing group and the placebo group on study day 15 (P < .05). These differences were not statistically different on either study day 21 or 44 for the 400-µg ABT-578 dose group. Neither the 200-µg nor the 800-µg ABT-578 groups were statistically different from placebo at any time. There appeared to be no correlation between ABT-578 doses and stimulation index or percentage change in the stimulation index over time. Although a trend appeared to be present in declining lymphocyte stimulation indices on days 3, 7, and 15 after administration of the 400-µg qd dose, the large intragroup variability precludes any definitive conclusion that high systemic exposures of ABT-578 suppress lymphocyte proliferation. Furthermore, the lack of apparent relationship to the dose of ABT-578 and the absence of clinical correlation strongly suggest that such a trend is not clinically significant.
Safety
The percentages of subjects reporting 1 or more adverse events were 33%, 38%, 31%, and 25% for the placebo, 200-µg, 400-µg, and 800-µg qd dose groups, respectively. The major adverse events reported were pain, headache, injection site edema, injection site pain, injection site reaction, and localized desquamation due to dry skin and were mild in severity. No clinically significant laboratory test abnormalities that were considered to be related to the study drug treatment were detected. There were no clinically relevant changes in blood pressures, ECG, pulse rates, or body temperatures in individuals during the study. The lymphocyte subsets and IgG showed an unremarkable difference in all treatment groups as compared to placebo. Specifically, no subject had an absolute CD3+/CD4+ count below 200 µL(mm3), a value consistently associated with an enhanced risk of infection in immunocompromised individuals.14 Therefore, ABT-578 does not appear to affect the immunocompetency activity of healthy subjects over the studied doses and over the study period (44 days), a conclusion supported by the absence of any clinical correlation.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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following a single 900-µg dose of ABT-578 was estimated to be 254 ng·h/mL. To evaluate safety at systemic exposures beyond the 900-µg dose, this study of multiple-dose administrations of IV ABT-578 was performed. The highest dose selected for this study (800 µg qd for 14 days = total chronic dose of 11 200 µg) is much greater than the likely dose from a coronary drug-eluting stent (390 µg = one 28-mm stent and one 11-mm bailout stent; stent loading of 10 µg ABT-578 per millimeter of stent length) implanted in an individual during clinical trials. In this study, the mean all-day AUC0- achieved following daily administration of 800 µg ABT-578 for 14 days was 2395 ng·h/mL. This is approximately 10-fold higher exposure than that achieved at the highest dose administered in the single-dose escalation study.16 Sirolimus is known to distribute largely into erythrocytes, and whole-blood concentrations are used to determine the pharmacokinetics of sirolimus.17 Preclinical studies have shown that ABT-578 has a similar high blood-to-plasma ratio. When studies were conducted with [3H]-ABT-578 in human whole blood, the blood cell concentrations were approximately 10 to 30 times higher than the plasma concentrations.18 Therefore, to determine the pharmacokinetics of ABT-578, its concentration in whole blood was measured.
The current study showed that over the studied dose regimens, the assessment of ABT-578 systemic exposures, on day 14, showed dose proportionality with regard to Cmax and AUC. Over the studied dose range, minor deviations in proportionality (less than about 14%) were observed between doses. However, due to the limitation of the parallel group comparisons, the deviation from proportionality by an individual dose was considered clinically unimportant. The estimated mean half-life of ABT-578 by compartmental methods ranged between 25 and 31 hours. This was in agreement with the 26- to 40-hour half-life seen in the single-dose escalation study calculated by noncompartmental analysis.16 The trough concentrations measured on days 10 through 14 did not show fluctuation. The day 10 trough concentration was not significantly different from the day 14 trough concentration. Thus, steady state was reached by ABT-578 on or before day 10, the first day when a trough concentration was measured. This is consistent with the observed half-life of 25 to 31 hours in this study. The mean clearance of ABT-578 ranged from 4.0 to 4.6 L/h and is much lower than hepatic blood flow. The partitioning of the drug and its binding to erythrocytes is probably the restrictive parameter in low clearance and long half-life of this drug.
Variability in pharmacokinetic parameters of ABT-578 following multiple intravenous dosing was low. The coefficient of variation for Cmax and AUC, on average, was approximately 15%. These data are in contrast to the high variability observed in sirolimus pharmacokinetics, which is mainly attributed to its highly variable absorption following oral administration.
A traditional method of testing time linearity was not used for this study, as the study design was not optimal for characterizing AUC0- on day 1 because of the long half-life of ABT-578. The study was designed to maximize the total administered dose over 14 days. Although the study was not designed to allow rigorous noncompartmental assessment of time linearity, the fitting of a compartmental model to data from all days for each subject was adequate to demonstrate the absence of significant deviations.
The current study showed that only about 0.1% of the administered dose is excreted in the urine as unchanged parent drug. This observation is consistent with preclinical studies with ABT-578. The in vitro metabolism study with hepatocytes from rat, dog, monkey, and human showed that ABT-578 was significantly metabolized by cytochrome P-450 3A isozymes,17 and an ADME study in rabbit showed that only a minor fraction of intravenously administered dose was excreted in urine as nonpolar components.18 Sirolimus is also known to be highly metabolized, and the primary clearance route for its metabolites is biliary.19 In the ADME study in which a single dose of radioactive sirolimus was administered to healthy volunteers, 91% of sirolimus metabolites were found in the feces, and only 2% of metabolites were found in the urine.20
ABT-578 in qd multiple doses of 200, 400, and 800 µg was generally well tolerated by the subjects. Even with very high exposures attained in this multiple-dose study, no clinically significant changes in physical examination, vital signs, or laboratory measurements were observed during the course of the study. Specifically, no subject displayed any clinical or biochemical evidence of QTc prolongation, changes in lymphocyte subsets, or clinically serious adverse events. No differences were seen among the doses with respect to adverse event profiles or overall drug safety.
There appeared to be a trend in declining lymphocyte stimulation indices on study days 3, 7, and 15 after administration of 400 µg of ABT-578. However, no such changes were seen on days 21 and 44. In addition, no significant decline in lymphocyte stimulation indices was seen after administration of either 200 or 800 µgof ABT-578 at any time. We believe that this was related to the high variability observed in the mitogen-stimulated lymphocyte proliferation assay. This assay employed a process of washing the PBMCs following their collection and incubation of the washed cells in the absence of added ABT-578. As a result, the immunosuppressive response in the assay was dependent on intracellular accumulation of ABT-578 in PBMCs, presumably acquired during the preceding in vivo exposure. The extent of penetration and binding of ABT-578 in PBMCs is not known. In addition, the radioactive thymidine incorporated in PBMCs was measured 96 hours following the beginning of incubation, when most of the penetrated drug may have been lost. Therefore, we suspect that although there are some indications of immunosuppressive activity of ABT-578, limitations of this assay preclude any definitive conclusion that ABT-578 suppresses lymphocyte proliferation over the studied doses and duration.
In conclusion, ABT-578 is shown to be a safe drug at very high systemic exposures. Systemic exposure following implantation of the ABT-578 eluting stent is expected to be considerably lower when compared to the exposures seen in the current study. Further evaluation of the safety, pharmacokinetics, and efficacy of ABT-578 when administered from the stent is ongoing in phase II and III clinical trials.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Ajani AE, Kim HS, Waksman R. Clinical trials of vascular brachytherapy for in-stent restenosis: update. Cardiovasc Radiat Med. 2001;2: 107-113.[CrossRef][Medline] [Order article via Infotrieve]
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7. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents verses standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349: 1315-1323.
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10. Chen Y, Gintant GA, Cox BF, Sullivan J. Comparison of Potencies of ABT-578 and Rapamycin in Inhibiting Human Coronary Artery Smooth Muscle Cell Proliferation. Abbott Laboratories, Internal Scientific Report No. R&D/02/386. Abbott Park, Ill: Abbott Laboratories; 2002.
11. Chen Y, Burke S, Toner J. Comparative Potency of ABT-578, Sirolimus, Everolimus, Tacrolimus, Paclitaxel, and Dexamethasone in Inhibiting Human Coronary Artery Smooth Muscle Cell Proliferation In Vitro. Abbott Laboratories, Internal Scientific Report No. 51R-002-AP-03-R1. Abbott Park, Ill: Abbott Laboratories; 2004.
12. Burke SE, Toner JL, Cromack KR, et al. ABT-578, paclitaxel, and rapamycin-eluting stents show similar efficacy in a porcine model of coronary restenosis. Poster presented at: Annual Meeting of Cardiovascular Revascularization Therapies (CRT); March 2005; Washington, DC.
13. Ji QC, Reimer TM, El-Shourbagy TA. 96-Well liquid-liquid extraction liquid chromatography-tandem mass spectrometry method for the quantitative determination of ABT-578 in human blood samples. J Chromatogr B. 2004;805: 67-75.
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16. Palaparthy R, Pradhan RS, Chan J, et al. Safety and pharmacokinetics of single, escalating, intravenous doses of ABT-578 in healthy male subjects [abstract]. AAPS J. 2004;6: M1096.
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18. McCracken NW, Darbyshire JF, Roberts SA. In Vitro Distribution of [3H]A-179578 in Human Whole Blood. Internal Scientific Report No. R&D/03/811. Abbott Park, Ill: Drug Metabolism Division, Abbott Laboratories; 2004.
19. Murray B, Medina C, Guan Z, et al. The Metabolism, Excretion and Tissue Distribution of [14C] Abbott-179578 in Rabbits. Internal Scientific Report No. R&D/03/366. Abbott Park, Ill: Drug Metabolism Division, Abbott Laboratories; 2002.
20. Wyeth Laboratories. Sirolimus (Rapamune) [prescribing information]. Philadelphia: Wyeth-Ayerst Pharmaceuticals; 2001.
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