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DRUG INTERACTIONS |
From Wyeth Research, Collegeville, Pennsylvania, and Cambridge, Massachusetts.
Address for correspondence: Joseph Boni, PhD, Director, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426; e-mail: bonij{at}wyeth.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Temsirolimus • cytochrome P450 • CYP3A • rifampin • pharmacokinetics
Temsirolimus (CCI-779) is a novel selective inhibitor of the mammalian target of rapamycin (mTOR), which regulates cell growth and proliferation by controlling translation of cell cycle regulatory proteins.5,6 In addition, mTOR upregulates expression of hypoxia-inducible factor (HIF) and HIF target genes, including the proangiogenesis factor vascular endothelial growth factor.7,8 Temsirolimus is in clinical development for the treatment of various malignancies, including renal cell carcinoma and mantle cell lymphoma.9-14 Pharmacokinetic (PK) profiles of temsirolimus in cancer patients are established.15-18
Various rapamycin analogs, including tacrolimus and everolimus, exhibit CYP3A-mediated drug interactions.19-21 In vitro metabolism studies in human liver microsomes indicate that sirolimus is an equally potent metabolite of temsirolimus and is present in the circulation to an appreciable amount relative to the parent drug.15-18 Both temsirolimus and sirolimus are metabolized by the CYP3A isoenzymes. Chemical structures of temsirolimus and sirolimus are shown in Figure 1. Because temsirolimus and sirolimus are both substrates for CYP3A, the potential exists for clinically significant metabolic drug interactions with coadministered CYP3A inducers. A phase I PK study of temsirolimus in patients with recurrent malignant glioma who were taking enzyme inducers provided initial clinical evidence suggesting the potential for drug interaction.22
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We investigated the effect of concomitant CYP3A inducers on the PK parameters of temsirolimus and sirolimus in 2 separate studies. The first study explored and compared the pharmacokinetics of intravenous (IV) temsirolimus in patients with advanced solid tumors who were taking enzyme inducers and those who were not taking enzyme inducers. The second study, conducted in healthy adults, defined the effect of rifampin coadministration on temsirolimus PK profiles after a single IV or oral dose of temsirolimus.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Patients with nonoperable and/or recurrent malignant gliomas or brain metastases from solid tumors were enrolled. The enrolled patients were separated into 2 groups: those who were receiving an enzyme-inducing anticonvulsant agent (carbamazepine, phenytoin, or phenobarbital/primidone, with or without high-dose dexamethasone) and those not on such medications. If patients received an enzyme inducer within 30 days of the first temsirolimus dose, they were considered to be in the enzyme inducer group. Patients not meeting this criterion were considered for the control (noninducer) group. Part 1 was a dose escalation study to evaluate the safety, tolerability, and pharmacokinetics for patients with advanced solid tumors. For pharmacokinetic statistical analyses, 9 patients from study part 1 who were not receiving an enzyme inducer and who received weekly doses of 220 mg/m2 temsirolimus were added to the noninducer group. Data from part 1 were previously reported.18
The protocol was approved by all institutional review boards (IRBs) of the following investigational sites: University of Düsseldorf, Germany; Ninewells Hospital and Medical School, Dundee, United Kingdom; University of Dresden, Germany; and University Hospital, Hamburg, Germany. The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. All patients gave written informed consent prior to participation.
Eligible patients were aged 18 years or older, with measurable or evaluable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, life expectancy of at least 3 months, normal blood counts, and adequate renal and hepatic functions. Patients were excluded if they had received prior chemotherapy and/or radiation therapy or another investigational agent within 4 weeks (6 weeks since nitrosoureas and mitomycin C) of study initiation, or if they were immunocompromised, including known infection with human immunodeficiency virus or use of immunosuppressive agents within 3 weeks before study entry (except for corticosteroids used as antiemetics or to reduce edema in patients with primary or metastatic central nervous system [CNS] tumors). Patients with unstable angina, recent myocardial infarction (
6 months before study enrollment), or use of ongoing maintenance therapy for life-threatening arrhythmia were excluded, as were patients with known hypersensitivity to macrolide antibiotics (eg, clarithromycin, erythromycin, azithromycin).
All patients received the maximum acceptable dose established in part 1 of the study (220 mg/m2 temsirolimus administered once weekly as a 30-minute IV infusion). Whole-blood samples for the quantification of temsirolimus and sirolimus in blood were collected prior to the first temsirolimus administration (0 h), then at 0.25 (during infusion), 0.5 (end of infusion), 1, 2, 4, 6, 24, 72, 96, and 168 hours after the start of infusion. The same PK time points were assessed during a subsequent temsirolimus infusion (
week 3). The bioanalytic assay has been previously published.18
Patients received temsirolimus for up to 8 or 16 weeks, depending on tolerance and whether clinical benefit (complete response, partial response, or stable disease)23 was observed. To receive the next weekly dose at the same dose level at the scheduled time, patients could not have grade 3 or 4 toxicity as defined by the National Cancer Institute (NCI) Common Toxicity Criteria Version 2. A delay in treatment of more than 2 weeks because of toxicity was considered unacceptable, and patients were removed from the study.
Rifampin Study in Healthy Adults
This open-label, sequential, 2-period, parallel-group, inpatient/outpatient study evaluated the effects of multiple oral doses of the potent CYP3A4 inducer rifampin on the PK profile of a single 25-mg IV dose or a single oral 30-mg dose of temsirolimus in healthy adults. These doses were chosen as the highest that were expected to be tolerated by healthy subjects, and they were comparable to anticipated phase III dose levels of temsirolimus in patients with cancer. The study was reviewed and approved by the IRB of the investigational site, SeaView Research (Miami, Florida), and was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. All participants provided written informed consent prior to enrollment in the study.
Potential participants were healthy men and women aged 18 to 50 years with a body mass index (BMI) in the range of 18 to 30 kg/m2 and body weight of at least 50 kg. Participants were excluded if they had a history or clinical evidence of significant cardiovascular, hepatic, renal, respiratory, gastrointestinal, endocrine, immunologic, dermatologic, hematologic, neurologic, psychiatric, or other chronic disease; active alcoholism or drug abuse; or any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the test agents. Participants were not allowed to take any over-the-counter medication, including herbal medicine, for 14 days prior to study initiation. Consumption of any caffeine-containing products, grapefruit, grapefruit-containing products, or alcoholic beverages was not permitted within 48 hours of study initiation. Patients fasted for at least 10 hours before temsirolimus administration, and water was not permitted during the 2 hours before and after infusion. Consumption of standard medium-fat meals was started approximately 4 hours after dosing.
On the morning of day 1, participants were evaluated for vital signs, blood and urine chemistries, and 12-lead electrocardiogram (ECG) (including heart rate, rhythm, and PR, QRS, QT, and QTc intervals). Serial blood samples to determine temsirolimus and sirolimus whole-blood concentrations were collected before and after temsirolimus administration of either a single 25-mg dose via 30-minute IV infusion or a single 30-mg oral dose (three 10-mg tablets, taken with 240 mL of room-temperature water). Whole-blood samples for temsirolimus and sirolimus concentrations were collected at 0 (predose), 0.5, 1, 2, 3, 8, 24, 48, 72, 96, 120, 144, and 168 hours. Those participants receiving IV temsirolimus were premedicated with IV diphenhydramine 25 mg. All participants were discharged on day 8, after the blood collection at 168 hours, and were instructed to return to the study site daily during the mornings of study days 15 through 19 to receive a single 600-mg oral dose of rifampin (two 300-mg capsules, taken with 240 mL of room-temperature water).
Participants remained at the study site from days 20 through 28. On day 20, predose blood samples were collected, and each participant received a single 600-mg oral dose of rifampin. On day 21, each participant was administered either a 25-mg IV dose of temsirolimus or a 30-mg oral dose of temsirolimus, both with an oral dose of 600-mg rifampin. Serial blood samples for PK analyses were obtained after dosing at the same time intervals as on day 1. All participants received oral doses of rifampin daily on study days 22 through 27. Participants were discharged on day 28, after the 168-hour blood collection. Physical examinations, vital sign and clinical laboratory measurements, 12-lead ECG, and urine drug screen were performed on day 34. Treatment-emergent adverse events (TEAEs) were reported by the investigator as mild, moderate, or severe.
Bioanalytic Methods
Blood samples were collected in evacuated collection tubes containing EDTA and stored at -70°C. Whole-blood concentrations of temsirolimus and sirolimus were measured by Taylor Technology (Princeton, New Jersey), using a stable, validated dual-range procedure. Temsirolimus, sirolimus, and their respective internal standards, d7 CCI-779 and 32-desmethoxyrapamycin, were coextracted from a 0.2-mL sample into 1-chlorobutane using a liquid-liquid method. Extracts were chromatographed using a YMC ODS AQ high-performance liquid chromatography (HPLC) column, with methanol and water containing ammonium acetate and acetic acid used as the mobile phase solvents. Analytes were quantified by tandem mass spectrometry using atmospheric pressure chemical ionization. Precursor and product ions were respectively monitored for temsirolimus at 1047.7 and 980.6 atomic mass units (amu), for d7 CCI-779 at 1054.9 and 987.7 amu, for sirolimus at 931.6 and 864.5 amu, and for desmethoxyrapamycin at 901.6 and 834.5 amu. A linear function was fitted to the calibration data using a weighted (1/concentration2) linear least squares regression procedure. The low-range and high-range assays were validated from 0.25 to 25 ng/mL and from 2.5 to 2500 ng/mL, respectively, for temsirolimus and from 0.25 to 25 ng/mL and from 2.5 to 250 ng/mL, respectively, for sirolimus. Precision and bias of temsirolimus quality control samples were 9.07% and -10.8% for the low-range assay, respectively, and 12.5% and -16.6%, respectively, for the high-range assay. Precision and bias of sirolimus quality control samples were 10.4% and -6.33%, respectively, for the low-range assay, and 15.8% and -13.7%, respectively, for the high-range assay.
Pharmacokinetic and Statistical Analysis
Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to Cmax (tmax), terminal elimination half-life (t
), area under the concentration-time curve truncated at the last observed whole-blood concentration (AUCT), total AUC, clearance (CL for IV and CL/F for oral treatment), and volume of distribution (Vdss for IV and Vz/F for oral treatment) were calculated using standard noncompartmental methods.24 The ratio of sirolimus to temsirolimus AUC (AUCratio) and the sum of the AUCs of temsirolimus and sirolimus (AUCsum) were calculated, unadjusted for differences (
13%) in molecular weight.
All pharmacokinetic parameters were summarized using descriptive statistics. For the study in cancer patients, testing of PK parameters between the first temsirolimus dose (cycle 1, week 1) and repeated doses (subsequent cycle) for a period effect was performed using a 2-factor analysis of variance (ANOVA) on log-transformed data and implemented through SAS (SAS Language Reference, Version 8, 1999, SAS Institute, Inc, Cary, North Carolina). For assessment of effect by treatment, statistical testing for comparison of PK parameters between groups was performed using a 2-sample t test. Statistical differences of P < .05 were considered significant.
For the rifampin study, least squares geometric mean (LSGM) ratios between test and reference treatments, as well as their 90% confidence intervals for Cmax, AUCT, and AUC, were determined from ANOVA using the WinNonlin Enterprise application Version 4.1 software (Pharsight Corp, Mountain View, California). A sample size of 16 subjects assigned to receive each route of temsirolimus administration was selected based on practical considerations. The magnitude of the effect of rifampin on temsirolimus or sirolimus exposure was estimated using the 2 one-sided tests bioequivalence procedure on log-transformed Cmax, AUCT, and AUC values.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Analysis
Whole-blood samples were obtained from all 16 patients during cycle 1 (week 1) who received the 220-mg/m2 temsirolimus dose (range, 334-514.8 mg) and from 12 patients during a subsequent cycle (week 3) who received doses ranging from 147 to 220 mg/m2 (270-512.6 mg). Doses less than 220 mg/m2 represent patients who required dose reductions. The mean duration of treatment was 1.3 months (range, 0-3 months), and a mean of 5.8 doses (range, 1-14 doses) were administered.
Pharmacokinetic parameters for temsirolimus and sirolimus are summarized in Table II. For most parameters, means were similar for cycle 1 and subsequent cycles. One exception was for temsirolimus Cmax, in which peak concentrations tended to increase by approximately 51% with continued weekly therapy (P = .04).
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To explore the effect of enzyme inducers on temsirolimus disposition, data were segregated based on presence or absence of concomitant enzyme inducers (Table III). For this statistical analysis, 9 patients from study part 1 (dose escalation) who were not receiving an enzyme inducer but who received temsirolimus 220 mg/m2 were added to the noninducing group (Table I). Comparison of PK parameters when temsirolimus was coadministered with an enzyme inducer versus noninducer indicates that the temsirolimus Cmax decreased by 36% (P = .02), and Vdss increased by 99% (P = .05). Sirolimus Cmax decreased by 67% (P < .001), AUC decreased by 43% (P = .05), and AUCsum decreased by 34% (P = .03). No significant PK differences between inducer and noninducer groups were observed upon the subsequent cycle (data not shown), but the limited number of observations precluded an effective comparison.
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Adverse Events
All 16 patients reported at least 1 TEAE, most commonly NCI grade 2 or less. The most frequently occurring TEAEs (all grades [grade 3 or 4]) were thrombocytopenia (63% of patients [25%]), anemia (56% [6%]), hypercholesterolemia (56% [31%]), hyperlipidemia (44% [6%]), increased aspartate aminotransferase (AST; 38% [0%]), leukopenia (38% [6%]), and stomatis/mucositis (31% [6%]).
Antitumor Response
One patient experienced partial response, 7 had stable disease (6 weeks), 7 had progressive disease, and 1 was not evaluable for efficacy. The partial response occurred in a patient initially diagnosed with anaplastic astrocytoma, was first noted on day 50 and confirmed on day 77, and had a duration of 0.9 months. The median time to tumor progression for all patients was 2.0 months (95% confidence interval [CI]: 1.6, 3.1).
Effect of Rifampin on Pharmacokinetic Profile
Thirty-two healthy adults were enrolled in a study to explore the effects of concomitant rifampin on the temsirolimus PK profile; 16 were assigned to receive IV temsirolimus and 16 to receive oral temsirolimus. Baseline temsirolimus and sirolimus PK profiles were first obtained for participants in the absence of rifampin. Participants then received a 600-mg oral dose of rifampin daily for 6 days prior to and including the day that they also received a single administration of IV or oral temsirolimus and continued on rifampin for 8 subsequent days.
Baseline demographic characteristics of the study population are shown in Table I. Participants were primarily men (94%), mostly of Hispanic or Latino ethnicity and Caucasian (88%), and the mean age was 36 years (range, 20-50). Three participants did not complete the study: 1 failed to return on study day 20, 1 had a positive urine drug screen at admission on study day 20, and 1 withdrew consent with no reason specified. However, all available data for these participants were included in the PK analysis.
Intravenous Temsirolimus
Mean whole-blood concentrations of temsirolimus and sirolimus over time following a single 25-mg IV dose of temsirolimus are illustrated in Figure 2. For the analysis of temsirolimus, mean concentration-time profiles were similar for treatment with temsirolimus plus rifampin compared with temsirolimus alone (period 1). For the analysis of sirolimus, the mean concentration-time profile for treatment with temsirolimus and rifampin was lower than the profile for treatment with temsirolimus alone. Mean PK parameters are summarized in Table IV. The mean temsirolimus Cmax values were similar for both treatments. Mean sirolimus Cmax was 65% lower for treatment with temsirolimus and rifampin than for treatment with temsirolimus alone.
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Mean time to maximal concentration (tmax) for temsirolimus was consistently at the end of infusion (0.5 h) with or without rifampin coadministration. In contrast, mean sirolimus tmax increased from 2 to 24 hours when rifampin was coadministered with temsirolimus (data not shown). Mean temsirolimus Vdss was comparable, with and without rifampin.
Mean temsirolimus half-life was generally unchanged by rifampin coadministration, although mean sirolimus half-life decreased from 69 to 55 hours when rifampin was coadministered. Nominal carryover of sirolimus metabolite from period 1 treatment into period 2 was observed for 12 out of the 15 participants. This carryover exposure accounted for approximately 9.7% of the total period 2 AUC.
Statistical comparisons demonstrated that, for temsirolimus, the 90% CIs for LSGM ratios of Cmax, AUCT, and AUC were in the range of 87% to 123% (Table V). For sirolimus, the 90% CIs for LSGM ratios of Cmax, AUCT, and AUC were lower and in the range of 31% to 52%.
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Oral Temsirolimus
Following a single 30-mg oral dose of temsirolimus, mean blood concentrations of both temsirolimus and sirolimus were lower with rifampin coadministration than with temsirolimus alone (Figure 3, Table IV). Values for mean Cmax decreased 41% for temsirolimus and 63% for sirolimus. Mean AUC values decreased 30% for temsirolimus and 60% for sirolimus. The variability of values for Cmax and AUC was moderate (41%).
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Results from the statistical comparison (Table V) indicated that the 90% CI for LSGM ratios of Cmax, AUCT, and AUC for both temsirolimus and sirolimus were below the predefined lower confidence limit of 80%. Respective LSGM values were 59%, 67%, and 71% for temsirolimus, and all LSGM values were 40% for sirolimus.
Adverse Events
Safety analyses included data from all 32 participants, each of whom received at least 1 dose of temsirolimus. Treatment-emergent adverse events occurred in 81% of participants. In general, more TEAEs occurred in participants receiving IV temsirolimus than in those receiving oral temsirolimus. For healthy subjects, TEAEs, expressed as n (%) alone vs + rifampin, observed in at least 10% of subjects receiving the 25-mg IV dose of temsirolimus included headache, 8 (50) vs 2 (13); stomatitis/mucositis, 13 (81) vs 6 (40); acne, 5 (31) vs 0; pain, 2 (13) vs 1 (7); high creatine phosphokinase, 0 vs 1 (7); pharingitis, 4 (25) vs 0; rash, 2 (13) vs 1 (7); high triglycerides, 2 (13) vs 0; and arthralgia, 2 (13) vs 1 (7). For healthy subjects receiving the 30-mg oral dose of temsirolimus, TEAEs observed in at least 10% of subjects included headache, 0 vs 1 (7); stomatitis/mucositis, 0 vs 0; acne, 2 (13) vs 0; pain, 0 vs 1 (7); high creatine phosphokinase, 0 vs 1 (7); pharingitis, 0 vs 0; rash, 0 vs 0; high triglycerides, 2 (13) vs 0; and arthralgia, 0 vs 0.
Overall, incidence of any adverse event following 25-mg IV temsirolimus was 15 (94) vs 12 (80) and, following 30-mg oral temsirolimus, 3 (19) vs 3 (20).
All adverse events were considered to be mild or moderate by the investigator and were resolved by completion of the study. Overall, 19 (60%) participants had 1 or more mild TEAEs, and 5 (22%) participants had 1 or more moderate TEAEs. There were no serious adverse events, discontinuations due to TEAEs, or deaths.
During the period when participants received rifampin alone, only headache and elevations in creatine phosphokinase occurred in more than 1 participant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In the exploratory study of temsirolimus in patients with advanced solid tumors, weekly administration of 220 mg/m2 IV was tolerated, and antitumor activity was observed. However, concomitant enzyme-inducing medications decreased temsirolimus Cmax by 36% and increased Vdss 99%. Exposure to sirolimus modestly exceeded that of the parent drug and was substantially more affected by enzyme inducers; sirolimus Cmax decreased by 67%, and AUC decreased by 43%. It is acknowledged that use of separate subjects on and not on enzyme inducers, however, may be problematic because of the nature of the wide variability of CYP3A activity in humans, and the patient findings should be viewed with caution. Notwithstanding, these results are not inconsistent with a previous report of a 1.6-fold lower AUC for sirolimus, as well as a lack of effect for temsirolimus, in patients taking enzyme inducers.22 Although temsirolimus dosage adjustment did not appear to be required in this study, the PK alterations observed are consistent with CYP3A-mediated drug interaction mechanisms.
In an effort to address limitations of the cross-study comparisons made in the patient study, a more definitive crossover study in healthy adults was performed. This study demonstrated that coadministration of the potent CYP3A inducer rifampin had no effect on IV temsirolimus Cmax and AUC but decreased sirolimus Cmax by 65% and AUC by 56%. Compared with oral temsirolimus treatment alone, concomitant rifampin decreased temsirolimus Cmax and AUC by 41% and 30%, respectively, and decreased sirolimus Cmax and AUC by 63% and 60%, respectively. The combined AUC for temsirolimus and sirolimus (AUCsum) was suppressed with both IV (41%) and oral (57%) administration of temsirolimus with concomitant rifampin.
Rifampin is known to upregulate both the hepatic and intestinal metabolic activity of CYP3A4.25 The results of this study indicate that the induction effect of rifampin was more pronounced in the first-pass metabolism of oral temsirolimus compared with the metabolism of IV temsirolimus. The extent of rifampin-mediated induction on the hepatic metabolism of sirolimus appeared to be similar following IV and oral routes of temsirolimus administration.
Temsirolimus was well tolerated when given to healthy adults either as an IV or oral dose, whether alone or in conjunction with oral rifampin. All of the most frequently occurring TEAEs in this study were considered to be mild or moderate in severity and included (mild and moderate [moderate]) stomatitis/mucositis (50% [3%]), headache (41% [6%]), and acne (22% [3%]). There were no adverse events considered to be treatment related in these healthy trial participants that had not been reported in repeat-dose studies of temsirolimus in patients with cancer.9-12,14
In conclusion, substances that are potent inducers of CYP3A activity decrease drug exposure following administration of temsirolimus. If agents with CYP3A induction potential must be used, an increase in temsirolimus dosage should be considered to minimize the risk of subtherapeutic temsirolimus levels.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This research was supported with funding from Wyeth Research, Collegeville, Pennsylvania. All authors are employees of Wyeth Research.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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