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Originally published as JCO Early Release 10.1200/JCO.2003.08.092 on September 29 2003 © 2003 American Society for Clinical Oncology Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies
From the University of Leicester, Leicester, United Kingdom; Tumor Biology Center and Freiburg University, Freiburg, and Schering AG, Berlin, Germany; and Novartis Pharmaceuticals, East Hanover, NJ. Address reprint requests to Bruno Morgan, MD, Academic Department of Radiology, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom; e-mail: bruno.morgan{at}uhl-tr.nhs.uk.
Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development.
IN ORDER to grow larger than 1 to 2 mm in diameter, solid tumors need to create a blood supply through the process of angiogenesis.1–3 Vascular endothelial growth factor (VEGF), a potent angiogenic factor, is released by a variety of normal and neoplastic cells4,5 following a hypoxic stimulus. VEGF also induces hyperpermeability of tumor vessels, which is a critical event in angiogenesis.6 Specific inhibition of tumor-induced angiogenesis should prevent the continued growth of many solid tumors, as well as prevent their metastatic potential, thereby providing a novel approach for the treatment of cancer.7 Inhibition of VEGF-induced angiogenic signals selectively targets tumor-associated vessels, since cell division of endothelial cells in the normal vasculature is a rare event. Antiangiogenic therapy targeted at the VEGF kinase receptor is thus expected to be safe and well tolerated in cancer patients. PTK787/ZK 222584 (PTK/ZK) is a potent, orally active and selective inhibitor of the VEGF-receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR-2 (KDR), under codevelopment by Novartis Pharmaceuticals (East Hanover, NJ) and Schering AG (Berlin, Germany). PTK/ZK has been shown to inhibit growth and reduce microvasculature in subcutaneously implanted human tumor xenografts in nude mice.8–10 Its intended indication is for the treatment of patients with solid tumors known to overexpress VEGF and VEGF-receptor, including carcinomas of the gastrointestinal tract.11 Phase I studies are ongoing in evaluating the safety, pharmacokinetics, pharmacodynamic effects, and biologic activity of PTK/ZK in several advanced cancers including colorectal cancer, breast cancer, glioblastoma multiforme, prostate, and renal cancer where VEGF is known to play a role.12–15 Successful chemotherapy or radiotherapy will typically result in a reduction of the cross-sectional diameter of a tumor when measured on serial computed tomography scans, but these changes and their relationship to efficacy may be slow and unreliable.16,17 Measurement of the efficacy of targeted biologic agents, including inhibitors of angiogenesis, is even more difficult because these agents may not cause rapid involution of tumors2 and may simply slow or stop tumor growth. This provides a problem for a phase I study because the biologically active dose may be difficult to predict in humans, as it may be considerably lower than the maximum-tolerated dose of drugs having a safe toxicology profile. Dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) may be used to study the pathophysiology of tumors.18,19 Parameters of interest include microvascular density; vascular permeability; and the extravascular, extracellular space.20 Notably, malignancy, stage, and prognosis have all been correlated with these enhancement parameters.21–25 Several studies have shown that successful therapies also result in changes in DCE-MRI contrast-enhancement parameters, which may prove to be a more accurate and earlier indication of response.26–29 In animals, an antibody targeted against VEGF has been shown to rapidly reduce contrast enhancement as measured by DCE-MRI.30,31 Dose-related changes in the contrast-enhancement parameters on DCE-MRI were evaluated for its use as a biomarker to assess the pharmacologic response of escalating dose levels of PTK/ZK in two ongoing phase I clinical studies, recruiting adult patients with advanced cancers. Study PTK/ZK CPTK787 0101 (study 0101) enrolled patients with a variety of advanced cancers, while study PTK/ZK CPTK787 0103 (study 0103) enrolled patients with advanced colorectal and breast cancers with liver metastases. In addition, potential correlations of this parameter to pharmacokinetic end points (dose, drug plasma exposure [area under the plasma concentration curve {AUC}] and trough plasma concentration [Cmin]), and clinical end points (best tumor response and tumor shrinkage) were assessed. Although the primary objective of these phase I studies was to determine the dose-limiting toxicity and maximum-tolerated dose of PTK/ZK, a variety of pharmacodynamic parameters, including serum- or plasma-soluble factors of angiogenesis and activated endothelial cells and Doppler ultrasound of tumor lesions,32 in addition to DCE-MRI were assessed to better define a biologically active dose for further evaluation in phase II and III studies. This study reports on the results of DCE-MRI as a potential biomarker for PTK/ZK, as defined by an objective measurement indicating a pharmacological response to a therapeutic intervention.33
Patient Selection As PTK/ZK is intended to treat solid tumors known to overexpress VEGF and VEGF receptors, the patients enrolled on the two phase I studies were predominantly patients with advanced cancers, including colorectal cancers with liver metastases, and renal cell, breast, lung, and prostate carcinoma. To assess DCE-MRI changes with relation to dose and clinical effect, the results were analyzed by tumor subtype. This study reports the DCE-MRI and pharmacokinetic results of patients with advanced colorectal cancers with liver metastases (the largest patient subpopulation) who were treated with PTK/ZK on the dose-escalation phase of both studies, and who underwent the MRI protocol.
Patients with histologically confirmed advanced solid malignancies with no standard curative therapy were eligible for the studies. All patients were required to have at least one site of measurable or assessable disease as determined by the Southwest Oncology Group. Inclusion was irrespective of stage of disease or extent of prior therapy. Patient entry criteria included: age All patients were informed about the investigational nature of the study according to institutional and regional guidelines, and each patient subsequently signed an approved informed consent form before the start of the studies. Permission of local ethics regulatory bodies was obtained at each center.
Drug Administration and Study Design
Bioanalytical Assay
Pharmacokinetic Assessment
The pharmacokinetic parameters, AUC, maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and elimination half-life(t1/2) were determined for each individual plasma concentration-time data on day 1 and at the end of cycle 1 (EC1). The Cmax and Cmin were determined on day 1 and EC1 by visual inspection of each patient’s plasma concentration. Using the noncompartmental method (WinNonlin Pro 3.2; Pharsight Corp, Mountain View, CA), AUC0-
DCE-MRI Methodology Liver metastases undergo bulk motion during imaging due to respiration. To avoid long breath holds and to enable high temporal resolution, an imaging sequence used in cardiac perfusion studies was adapted.34–36 This was achieved using an inversion recovery gradient echo snapshot flash sequence (turbo FLASH). At both sites, the sequences used a matrix of 96 x 128, a slice thickness of 10 mm, and an effective inversion time (TI) of 815 ms (Freiburg: TR, 3.6 ms; TE, 1.7 ms; TI, 640 ms; and FA, 8°; Leicester: TR, 3.3 ms; TE, 1.4 ms; TI, 655 ms; and FA, 8°). A proton density (M0) sequence with no inversion pulse was performed at the beginning and end of the run to allow calculation of T1.37 The image acquisition time after a nonselective inversion pulse was approximately 350 ms. Low-molecular-weight gadolinium-chelate 0.1 mmol/kg (Magnevist; Schering AG, Berlin, Germany; or Omniscan; Nycomed, Roskilde, Denmark) was injected as a rapid bolus through an arm vein in less than 5 seconds. This injection speed was adhered to for all patients. The same contrast agent was always used for individual patients. Injection was commenced after the first four measurements to allow development of a steady state. The scans were performed with a temporal resolution of 3 seconds over 5 minutes. The coronal oblique plane and short image acquisition time successfully freezes respiratory motion and prevents the tumor from moving out of the slice during the 5-minute imaging time. This technique is sensitive to subtle changes in enhancement, and can measure T1 and thereby estimate gadolinium-chelate concentration throughout the range of enhancement expected for liver metastases.38 Signal intensities were taken from a region of interest (ROI) drawn around the tumor and aorta separately using the Analyze image manipulation package (Mayo Clinic, Rochester, MN). The position of the ROI was corrected on a time point–by–time point basis for any movement over time. In all cases, the profile of the tumor remained reasonably constant throughout the imaging sequence, so the ROI did not have to be altered in shape and volume. The bidirectional transfer constant (Ki, mL/100 g/min) was then calculated using a two-compartment model.34 As the imaging parameters are optimized for tumors rather than arterial enhancement, we used a standard data set for aortic input that was similar to that of previously published data.34,39 The timing of onset of the arterial input function was measured from the artery imaged in the study. Imaging data from the Freiburg site was sent to Leicester for analysis, so as to ensure uniformity and reproducibility of the data sets.
Tumor Assessments The best response criteria were used to categorize all assessable patients as either nonprogressors or progressors for the biomarker analysis in order to identify the differences in biologic effects in response to PTK/ZK. The best response was determined from the sequence of tumor response: CR, if two CR before progression (category 1); PR, if two PR before progression (category 2); SD, if two SD before progression (category 3); and PD, if one PD within the first 2 months of treatment (category 4). Nonprogressors were defined as belonging to categories 1, 2, and 3, while progressors were defined as belonging to category 4. No patient achieved a CR or PR.
DCE-MRI Statistical Methods and Modeling Using nonparametric statistics, the degree of association between % of baseline Ki and dose, drug plasma exposure (AUC), and Cmin were measured by the Spearman rank correlation coefficient. We calculated the mean % of baseline Ki and SE by time point (day 2 and EC1) for all doses and for doses of 1,000 mg or greater. Mean % of baseline Ki and SE by time point for progressors versus nonprogressors were also calculated. The % of baseline Ki distributions were compared using P values from the Mann-Whitney U test. P values, adjusting for baseline WHO performance status (WHOPS), were calculated by combining the WHOPS-specific exact P values using Fisher’s combination procedure. Using the Spearman rank correlation coefficient, we conducted a test of significance of the degree of association between the % of baseline Ki and percentage change in the bidimensional product of liver metastases after EC2. To describe the relationship between % of baseline Ki and exposure (AUC) in mathematical terms, pharmacodynamic modeling was performed by fitting the data to an inhibitory maximum effect (Emax) model:
where:
A weighting scheme of 1/Y was used. Although a clear association exists between % of baseline Ki versus dose, AUC, and Cmin, AUC is used in the modeling for the following reasons. First, the intent is to characterize the pharmacodynamic relationship of DCE-MRI to systemic drug exposure (AUC) without the influence of the dose-exposure relationship (which appears nonlinear and time-dependent) and associated variability. Second, the systemic drug exposure is adequately estimated by AUC, whereas Cmin is highly variable and does not accurately represent the plasma concentration at the time of DCE-MRI scan or the systemic drug exposure during a dose interval. In addition, to compensate for limited data points and the lack of data points on EC1 at the higher range of AUCs, the modeling was performed using pooled data from day 2 and EC1 in order to best characterize the entire inhibitory Emax curve. This should be plausible since the % of baseline Ki is highly correlated to AUC. This final model was selected based on Akiake’s information criteria, visual inspection, statistical estimation of the goodness of fit, and an understanding of the biology with antiangiogenic agents.
Patient Characteristics A total of 56 patients was enrolled in the dose-escalation phase from both studies. The number of patients by dose cohort for each study is listed in Table 1  . A total of 27 patients with advanced colorectal cancers were evaluated with MRI of their liver metastases. One patient treated at the 150-mg dose from study 0101 was excluded, as a different MRI protocol was used. The demographics for the remaining 26 patients with advanced colorectal cancers with liver metastases are listed in Table 2. All 26 patients were included in the pharmacokinetic analyses. Of these 26 patients, 4 patients did not complete cycle 1 treatment and were not assessable for tumor response due to reasons other than intolerable toxicity or disease progression. For the 22 remaining patients with assessable tumor response, 1 patient did not have the day 2 MRI scan performed, and 1 patient received less than 10 days of PTK/ZK treatment, and also did not have an assessable EC1 MRI scan that was taken 7 days after the last dose.
Pharmacokinetics The mean pharmacokinetic parameters, AUC, Cmax, and Cmin, are listed by dose groups and by day 2 and EC1 in Table 3 . PTK/ZK was rapidly absorbed following oral administration with a Cmax reached in 1 to 2.5 hours for all dose groups. At steady state, which was achieved by day 15, the systemic exposure (AUC) was approximately 30% lower than the exposure following a single dose for all doses above 150 mg. A representative PTK/ZK plasma concentration profile on days 1, 15, and 28 from a patient who received a dose of 1,200 mg PTK/ZK is shown in Figure 1. Metabolism via the CYP3A4 isoenzyme is the major elimination pathway, and autoinduction of this enzyme is likely the explanation for the observed decrease in AUC from day 1 to day 15. No further reduction in AUC was observed after day 15 and up to day 28. The half-life is approximately 3 to 6 hours for each dose group on day 2 and at EC1. PTK/ZK exposure seems to be dose proportional up to 1,000 mg on both day 2 and at EC1; however, the exposure seems to be less than proportional above 1,000 mg (Fig 2).
DCE-MRI Results The rapid reduction in enhancement within 26 to 33 hours after the first dose in a liver metastasis from colorectal carcinoma is visibly demonstrated in Figure 3 , with a relatively constant profile of the tumor, despite respiratory movement in the inferosuperior plane. As shown in Figure 4, this substantial reduction in enhancement is evident across all dose groups on day 2, with a mean reduction of Ki of 43% (SE, 6.95%). In the higher doses ( 1,000 mg), at which the maximum exposure is achieved, the reduction in enhancement is expectedly greater, with a mean reduction of Ki of 58% (SE, 5.2%) on day 2% and 53% (SE, 6.63%) at EC1. Using nonparametric statistics, a significant negative relationship was found between increasing PTK/ZK dose, AUC, and Cmin with reducing enhancement on both day 2 and EC1. Spearman rank correlation coefficients and significance values are listed in Table 4.
Of the 22 patients with assessable tumor response 21 had DCE-MRI at day 2 and EC1. There were 12 nonprogressors and 9 progressors. As shown in Figure 5 , nonprogressors had a significantly greater reduction in enhancement on day 2 and at EC1 compared with progressors (mean difference in % of baseline Ki 87% minus 40% equals 47%, P = .004 [day 2]; and % of baseline Ki 99% minus 48% equals 51%, P = .006 [EC1]). Of the nonprogressors, there were 10 patients with assessable MRI scans on both EC1 and EC2. All of these 10 patients maintained the pharmacodynamic effect as indicated by a non–statistically significant change in % of baseline Ki from EC1 to EC2 (% of baseline Ki [EC1], 50%; % of baseline Ki [EC2] = 41%; P = .275, Wilcoxon signed rank test), which suggests a strong relationship between % of baseline Ki and disease status. Furthermore, the difference in enhancement remained statistically significant after adjusting for baseline WHO performance status (adjusted P values of .013 [day 2] and .011 [EC1]). In addition, Figure 6 shows the strong relationship between the percent of baseline Ki on day 2 and EC1 compared with the change in liver disease size at the end of EC2, as measured by the change in the sum of measurable liver lesions, calculated by the bidimensional product of disease on MRI. Correlation is obtained for a day 2 Ki of 0.61 (P = .004) and EC1 Ki of 0.75 (P = .0001). In the case of progressive disease, in which the patient was "off study" by EC2, the size change at EC1 was used.
The inhibitory Emax model defines the mathematical relationship between % of baseline Ki and AUC (Fig 7 ). All 26 patients were included in the analysis on either or both day 2 and EC1. The estimated pharmacodynamic parameters are: E0 = 108% of baseline Ki (SE, 17.7; CV%, 16.38), estimated AUC50 = 39 hours*µM (SE, 25.24; CV%, 64.47), and Emax = 14.9% of baseline Ki (SE, 9.97; CV%, 66.76). The parameter E0 is estimated to be slightly greater than 100% because of a few patients having very large % of baseline Ki values. The relationship between a drug and the biologic response is usually quite complex, and in most cases, it can be described by a saturable system, such as the Emax model. This system obeys a linear relationship in response, between 20% and 80% of maximum response, with smaller increments in response at higher exposure until a maximum response is achieved. In the case of PTK/ZK, the reduction in enhancement decreases linearly with exposure (on a log scale) until approximately 200 hours*µM is reached. Thereafter, a less than proportional reduction in enhancement is achieved, with increasing exposure until the maximum effect is reached ( 15% of baseline Ki), at an exposure of approximately 450 hours*µM. Figure 7 suggests that most nonprogressors at both day 2 and EC1 achieved an exposure of 50 hours*µM — an exposure corresponding to the lower limit of the SD for the 1,000-mg dose at EC1. This is consistent with the finding that most nonprogressors received at least a 1,000-mg dose of PTK/ZK.
PTK/ZK was shown to cause a significant reduction in DCE-MRI contrast enhancement parameters within 26 to 33 hours of administration of the first dose. The extent of reduction was dose dependent at both day 2 and EC1. There was a statistically significant relationship between reduction in contrast enhancement and disease response. The exact mechanism of the reduction in enhancement is not clear. Gadolinium-chelate (Gd-chelate) uptake is multifactorial20 not only depending on vascularity, but also on vascular permeability and the extracellular space. Due to the relatively small size of Gd-chelate, permeability may be so high that enhancement is mainly related to vascularity (flow-limited). Conversely, if permeability is low, enhancement will be permeability limited.40 Sophisticated analysis measuring both vascularity and permeability is possible using macromolecular contrast media, but these agents are not currently licensed for use in humans.41,42 Gd-chelate enhancement can, therefore, be considered to be related to a combination of microvascular density and permeability (product of both flow into the tissue vasculature, and extraction into the extravascular, extracellular space).43 In animal models, successful inhibition of VEGF receptors may result in a reduction in both permeability and vascularity within hours of treatment onset.44,45 The rapid reduction of enhancement within 33 hours could therefore be attributed to either a reduction in endothelial permeability to Gd-chelate and/or to a reduction in vascularity owing to removal of VEGF receptor signaling, as VEGF is a vascular survival factor. In this case, the maximum reduction in enhancement achieved is 85%, which suggests a marked antivascular effect. The Emax model suggests that complete shut down of enhancement cannot be achieved. The reason for this is not shown by this method, but it may be related to the level of angiogenesis and vessel maturity within the tumors. The data suggest that reduction in enhancement is associated with better clinical outcome, and reductions of 40% or more are associated with lesion size reduction. However, these figures are based on this particular MRI technique. If MRI is to be used to predict outcome in a wider sense, then standardized techniques are needed. There are numerous methods of evaluating contrast enhancement parameters. Currently, there is no complete consensus of the best method, although many studies use similar methods to estimate the transfer constant for Gd-chelate as it passes into the interstitial space.40 We use the method described by Larsson et al, and use the term Ki in units of mL/100 g/min.34,43 Different methods assuming a similar process include ktrans, kep, and k21. Although all imaging slices include a section of the aorta, the arterial input function was not measured because of saturation of the MRI signal caused by the high arterial concentrations of Gd-chelate immediately after the bolus injection. A standard data set was used as described in the Patients and Methods section. Although this did not allow for variations of hemodynamics between patients, the study involved changes from baseline enhancement, with each patient acting as their own control. The study does, however, assume that the pharmacokinetics of the bolus injection remain constant for individual patients throughout the study. The magnitude of the observed changes in Ki suggests that this was not a problem in this study. Furthermore, calculating Ki using a standardized aortic input has been shown to be a reproducible measurement of contrast enhancement in human breast tumors.46 Previous work on DCE-MRI21–29 concentrates mainly on tumors that can be easily immobilized. This is not practical for many phase I studies, as metastatic disease often manifests in areas of the body, such as liver and lung, which undergo motion due to respiration. Our technique, therefore, involves a rapid, single-slice technique in a coronal oblique plane designed to "freeze" patient movement and keep the measured tumor "in-slice," A high-resolution pixel-by-pixel analysis is not practical in this setting, and tumors are measured by a single ROI covering the whole tumor area in the slice. Although this technique is subject to errors due to heterogeneity of enhancement, the data are easy to obtain with good "signal-noise ratio." Furthermore, during treatment, the enhancement changes are a reflection of the biologic action in the whole tumor. Although enhancement patterns may be measured in terms of changes in signal intensity over a ROI, this is not ideal, as signal intensity is an arbitrary measurement based on the MRI machine settings. Many studies "normalize’ this value by dividing by the baseline signal before enhancement, but this does not take into account possible variations in the baseline signal due to changes in the physiological parameter, T1, secondary to treatment. It is therefore desirable to calculate the change in longitudinal relaxation rate R1 (1/T1) through the dynamic run, as this is directly related to the concentration of the contrast agent.47 We have demonstrated that our technique is sensitive to subtle changes in enhancement and can measure R1 throughout the range of enhancement expected for liver metastases.38 Although our technique involves a relatively high temporal resolution of 3 seconds, examination of the enhancement curves shows that the large changes in Ki seen in this study would be demonstrated with lower temporal resolution, allowing higher spatial resolution to be achieved.
We recognize that this is a developing field and that there are currently many alternative methods available for acquiring and analyzing MRI data. Although we have discussed potential limitations to our technique, the results are clear, as shown by their magnitude (visible changes on Figure 3 To our knowledge to date, this is the first human study to show the potential use of DCE-MRI as a biomarker for the biologic effect of an angiogenesis inhibitor targeting the VEGF receptor. It is known that such agents inhibit tumor growth, but do not necessarily induce tumor regression. Thus, it is increasingly important to identify biomarkers that demonstrate the required drug-target interaction, and the desired downstream biologic effects. In these two phase I studies, DCE-MRI was shown to be a reasonable predictor of clinical response, as evidenced by statistically significant relationships between the DCE-MRI parameter, % of baseline Ki, and many clinical parameters, such as tumor response and the extent of tumor shrinkage. Furthermore, the reductions in % of baseline Ki were maintained over time in nonprogressors, and were independent of baseline WHO performance status. Statistically significant relationships between % of baseline Ki with PTK/ZK dose, concentration, and exposure strongly supports that the desired biologic effect of PTK/ZK is likely the result of drug-receptor interaction (ie, reversible binding of PTK/ZK to the VEGF receptor). In addition, the inhibitory Emax model sufficiently describes the relationship between % of baseline Ki and exposure in mathematical terms. This model could be useful in selecting the biologically active dose for further evaluation in phase II and III studies. This would require the identification of a dose in which the lower limit (SD) of exposure is associated with at least 40% reduction in enhancement (60% of baseline Ki), a level that is associated with nonprogressive disease. As suggested previously, at least a 1,000 mg dose would be required to achieve this exposure and thereby, a sufficient reduction in enhancement for nonprogressive disease. The clinical evaluation of molecularly targeted therapeutic strategies can be facilitated and strengthened by the use of appropriate biomarkers that measure the pharmacologic response in humans. If further studies demonstrate the correlation of DCE-MRI (ie, day 2 response related effect) to the clinical end point, then DCE-MRI may have a wider impact, allowing early assessment of efficacy and improved clinical management of such antiangiogenesis therapies.
The authors indicated no potential conflicts of interest.
We thank Dirk Reitsma, MD, David Lebwohl, MD, and Christian Pfister, MD, from Novartis Pharmaceuticals for their support on this project.
Research support provided by Novartis Pharmaceuticals, East Hanover, NJ, and Schering AG, Berlin, Germany. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
1.5x the upper limit of normal [ULN], serum bilirubin 
was calculated on day 1 using the linear trapezoidal rule up to the last measurable data point, and then extrapolated to infinity. AUC0–24 was calculated on EC1 using the linear trapezoidal rule up to 24 hours postdose. The t1/2 on day 1 and EC1 was calculated by dividing 0.693 by ke (the elimination rate constant), which was calculated by the linear regression of the WinNonlin selected data points on the terminal log-linear portion of the plasma concentration–time curve. 
