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PHARMACOKINETICS |
From PPD Development LLC, Austin, Texas (Dr Hunt), and MGI PHARMA, INC, Bloomington, Minnesota (Ms Gallagher, Dr Cullen, Dr Shah).
Address for reprints: Ajit K. Shah, PhD, MGI PHARMA, INC, 5775 West Old Shakopee Road, Suite 100, Bloomington, MN 55437-3174.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: 5-HT3 receptor antagonist • palonosetron • chemotherapy-induced nausea • antiemetic agent • pharmacokinetics
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In clinical studies, a single IV dose of palonosetron in healthy subjects and cancer patients was associated with a biphasic decline in plasma concentrations, showing an initial rapid distribution phase followed by a slower elimination from the body.1-3 After administration of a single IV dose of palonosetron 10 µg/kg (fixed dose of approximately 0.75 mg), the mean plasma elimination half-life (t1/2) was approximately 40 hours in healthy subjects.1,3 Pharmacokinetics of palonosetron and its metabolite M9 have generally been shown to be linear over the IV dose range of 0.3 µg/kg to 90 µg/kg in healthy volunteers and cancer patients.1-3 After a single IV dose of 10 µg/kg [14C]-palonosetron, approximately 80% of the dose was recovered in the urine with palonosetron representing approximately 40% of the administered dose. Approximately 50% of palonosetron was metabolized to 2 primary metabolites: N-oxide-palonosetron (metabolite M9) and 6-S-hydroxy-palonosetron (metabolite M4), each having <1% of the 5-HT3 receptor antagonist activity of palonosetron.1,3 Two additional metabolites, found at very low concentrations, are presumed to be 6-keto-N-oxo-palonosetron (metabolite M5) and 6-keto-palonosetron (metabolite M6). Both renal and hepatic routes are involved in elimination of palonosetron from the body.4 In vitro metabolism studies suggest that CYP2D6 and, to a lesser extent, CYP3A and CYP1A2 are involved in the metabolism of palonosetron. In addition to a much longer half-life than other 5-HT3 receptor antagonists (40 hours vs 4 to 8 hours5-7), palonosetron also has a stronger 5-HT3 receptor-binding affinity in cultured neuroblastoma rat glioma cells (pKi = 10.45)8 than granisetron (pKi = 8.91),8 ondansetron (pKi = 8.39),8 or dolasetron (pKi = 7.6).9 These pharmacokinetic and receptor-binding affinity properties are thought to contribute to the prolonged protection against delayed nausea and vomiting following a single palonosetron dose in clinical studies of patients receiving moderately or highly emetogenic chemotherapy.3,10-12
In a dose-ranging phase II study2 with patients randomized to receive a single IV bolus dose of palonosetron (0.3, 1, 3, 10, 30, or 90 µg/kg) prior to the administration of highly emetogenic chemotherapy, the 4 highest doses (3, 10, 30, and 90 µg/kg) were similarly effective, producing a complete response rate of 40% to 50%. In 2 phase III trials,10,11 single IV doses of 0.25 mg (approximately 3 µg/kg) and 0.75 mg (approximately 10 µg/kg) were evaluated in patients receiving moderately emetogenic chemotherapy in which a 0.25-mg dose was found to be the minimum effective dose in prevention of acute and delayed emesis. The concentration response relationship for palonosetron is not known; however, the recommended dose of 0.25 mg results in plasma concentrations exceeding the pKi for binding of palonosetron to the 5-HT3 receptors in NG-108 cells in vitro (10.4 ± 0.18 M [Ki = 13.2 pg/mL or equivalent to 34.7 pg/mL when corrected for 62% human plasma protein binding]). The potential risk for both acute and delayed nausea and vomiting in patients receiving multiple-day emetogenic chemotherapy regimens, such as 3- to 5-day cisplatin-based therapy, is well known.13,14 It would appear that palonosetron could be particularly useful for those patients in which emetogenic risk lasts for several days. The safety, efficacy, and pharmacokinetics of multiple-day dosing of palonosetron in patients have not yet been established. The objective of this phase I study was to evaluate the safety and pharmacokinetics following IV administration of palonosetron 0.25 mg daily for 3 days in healthy male and female subjects.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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91 kg and were within 20% of their recommended weight, had a negative urine drug screen and a negative hepatitis B surface antigen test, and had not engaged in strenuous exercise for 72 hours before study entry. Subjects were ineligible if they had a history of any chronic disease or any clinically significant illness within 3 months of study entry, if they had a history of any cardiovascular abnormality (including chronic heart failure, congenital or acquired valvular disease), and for clinically notable findings from the medical history, physical examinations, vital signs, laboratory results, or electrocardiogram (ECG) measurements. Additional reasons for exclusion were lactation; contraindications to 5-HT3 receptor antagonists; use of any prescription medication (other than birth control) within 2 weeks of study entry or anticipated use during the study; use of any nonprescription medication, nutritional supplements, vitamins, or herbal-type products within 72 hours of study entry or anticipated use during the study; receipt of any investigational drug within 30 days of study entry; previous enrollment in any palonosetron study; donation of blood or plasma within 30 days of study entry; use of tobacco or nicotine products within 3 months of screening; history of drug or alcohol dependence (subjects were eligible if they consumed an average of 7 drinks/wk and did not consume alcohol during the 7 days before admission to the clinic); and a history of drug allergies. Negative results from a serum pregnancy test were required for all women at risk of pregnancy. Females of childbearing potential and nonsterile men had to use a medically acceptable method of contraception. The Research Consultants' Review Committee of Austin, Texas, approved the study, and all subjects signed informed consent forms before participation in the study. The study was conducted at PPD Clinical Development of Austin, Texas.
Study Design
This was a phase I, single-center, double-blind, randomized, placebo-controlled, parallel safety and pharmacokinetic study of a single IV dose of palonosetron 0.25 mg (Aloxi, Onicit) administered to healthy subjects daily for 3 consecutive days. Eight men and 8 women were enrolled; 12 subjects were randomized to receive palonosetron, and 4 were randomized to receive placebo (sterile normal saline). A 5-mL study drug solution was injected as an IV bolus over 10 seconds into a peripheral vein. Subjects received study drug each morning after an 8-hour fast. Aseptic procedures were used during the preparation and administration of palonosetron or placebo. Palonosetron was provided in 5-mL vials as a sterile, isotonic, buffered solution for IV administration.
Safety Assessments
Safety was evaluated by adverse event reporting throughout the study and by 12-lead ECG measurements taken at screening (ie, day -14 to day -4), day -2, days 1 and 3 (5 minutes before and 20 minutes after dosing), and at the end of the study confinement on day 4. Subjects also underwent 24-hour cardiac telemetry monitoring from 48 hours to 24 hours before dosing on day 1 to detect the presence of any arrhythmia. Changes in physical examinations (assessed at screening and day 4), vital signs (assessed at screening and on days 1, 2, and 3 within 40 minutes before dosing and 20 minutes, 1.5, 3.5, 5.5, 11.5, and 23.5 hours after dosing), and clinical laboratory tests of serum chemistry, hematology, and urinalysis (assessed at screening and day 4) also were used to evaluate safety.
Pharmacokinetic Assessments
A 5-mL sample of blood was collected in a 5-mL sodium heparin tube and inverted several times to mix. Blood samples were drawn from a peripheral vein from the arm opposite to the arm of drug administration. Blood draws were taken 2 minutes before drug administration (time 0) and at 1, 3, 5, 15, and 30 minutes and 1, 2, 4, 6, 12, and 24 hours after drug administration on days 1 and 3 and on day 2, 1 minute after dosing. Blood samples also were collected at 48, 96, 120, and 168 hours after drug administration on day 3 (ie, study days 5, 7, 8, and 10, respectively). Blood samples were centrifuged at 1000 to 1300g (3000 rpm) for 10 minutes at room temperature to separate the red cells from the plasma. The plasma was removed and transferred into a 5-mL labeled polypropylene tube and immediately stored in an upright position at -20°C. Plasma tubes were kept frozen at this temperature until assayed. Under these storage conditions, palonosetron and metabolite M9 are stable for up to 22 and 10 months, respectively. Samples were assayed within these storage periods.
Bioanalyses
The concentrations of palonosetron and its N-oxide metabolite (metabolite M9) were measured using a validated method: liquid chromatography coupled to tandem mass spectrometry (MS). In brief, palonosetron, metabolite M9, and internal standard (quinidine) were extracted from plasma using solid phase extraction (SPE). The SPE cartridges (Varian C2, 1CC) were primed with 1 mL methanol, centrifuged for 1 minute, then primed with 1 mL deionized water and centrifuged. To 0.5 mL of plasma sample, 0.5 mL of water and 100 µL of internal standard solution (approximately 2700 pg of quinidine) were added. After vortexing, an aliquot of 1 mL was loaded on the cartridges. After 10 minutes, the cartridges were centrifuged and then washed with 1 mL of deionized water. This was repeated twice. The cartridges were transferred to 10-mL conical glass tubes and eluted with 0.25 mL of an elution solution (1 g ammonium acetate, 500 mL of water, 1500 mL of acetonitrile, and 1 mL of formic acid). This was repeated once. The eluate was transferred into autosampler glass vials. The vials were placed in a vacuum centrifuge, and the solution was concentrated under vacuum for 15 minutes. The remaining eluate was transferred into glass inserts and placed in autosampler vials, and 20 to 30 µL was injected onto the column.
The high-performance liquid chromatography system was Jasco 1500, with Waters NovaPack Phenyl column (150 mm x 3.9 mm) with oven temperature maintained at 40°C (50°C for metabolite M9) and interfaced to the MS/MS detection (Quatro Ultima, micromass) in the positive electrospray ionization mode. The mobile phase consisted of water (1000 mL), acetonitrile (1000 mL), formic acid (17 mL), and ammonium acetate (2 g). The flow rate was 0.35 mL/min. The optimum MS parameters were cone voltage 22 V, collision energy 25 eV, amplifier voltage 650 V, and temperature of the desolvation 380°C. The positive ions were detected in the multiple reaction monitoring mode with precursor to product ion pairs as 297.3 
109.95 (for palonosetron), 313.35 126.0 (metabolite M9), and 325.2 184.0 (for internal standard). The run time was approximately 7 minutes, with retention times of internal standard, palonosetron, and metabolite M9 of 5.0, 5.5, and 6.0 minutes, respectively.
The assay had a dynamic range of 43.5 to 2036 ng/L for palonosetron and 10.7 to 502.4 ng/L for metabolite M9. The accuracy and precision of calibration standards for palonosetron were less than 7% at all concentrations and less than 9% for metabolite M9. The precision and accuracy for quality control samples (low, mid, and high) for palonosetron were less than 11% and within 5%, respectively. Precision for metabolite M9 concentrations ranged from 16% to 43%, and accuracy ranged from -3% to 23%, with higher variability at the low concentrations. All samples from subjects receiving palonosetron were analyzed. For the 4 subjects receiving placebo, 1 sample (on day 3, 1 minute postdose) was assayed to confirm the absence of palonosetron and metabolite M9.
Pharmacokinetic Analyses
Pharmacokinetic parameters for palonosetron and metabolite M9 were analyzed using noncompartmental methods using WinNonlin Professional (version 3.3). Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) was calculated by the linear trapezoidal rule. Maximum plasma concentration (Cmax) and time to Cmax (Tmax) was determined by visual inspection of the data. The terminal phase elimination rate constant (Kel) was determined from the slope of the concentration-versus-time data plot during the log-linear terminal phase by regression analysis, and t1/2 was calculated as 0.693/Kel. The accumulation ratio (R) was calculated as the ratio of day 3 to day 1 AUC0-24.
Statistics
Descriptive statistical analysis was performed on pharmacokinetic parameters. Natural log-transformed AUC0-24 and Cmax data using a linear mixed effects model with gender as a fixed effect and subject as a random effect were used to analyze differences between male and female subjects. Confidence intervals (CIs; 90%) for female to male AUC0-24 and Cmax ratios were calculated. Untransformed t1/2 and R values were compared between male and female subjects using a 2-sample t test. Statistical significance was set at P .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Safety
All 16 enrolled subjects were evaluable for safety. No serious adverse events or deaths were reported during the study, and no subject discontinued the study because of an adverse event. Six of the 12 subjects receiving palonosetron reported 11 adverse events, and 2 of the 4 subjects receiving placebo reported 2 adverse events. Adverse events reported by subjects receiving palonosetron were headache (n = 2), dysmenorrhea (n = 2), migraine (n = 1), musculoskeletal chest pain (n = 1), cough (n = 1), pharyngitis (n = 1), contact dermatitis (n = 1), dry skin (n = 1), and pruritus (n = 1); adverse events reported by subjects receiving placebo were contact dermatitis (n = 1) and injection site pain (n = 1). All events were assessed as mild, except for 1 reported headache and 1 reported migraine in the palonosetron group, which were both assessed as moderate in intensity and not related to study drug. Only 1 adverse event (mild pruritus) reported by 1 subject receiving palonosetron was considered possibly related to study drug. No laboratory findings were recorded as adverse events, and none of the abnormal results recorded at screening or at the end of the study were considered to be clinically significant. There also were no clinically significant changes from baseline in vital signs, physical examination, or ECG parameters. There was no notable change from baseline in Bazett-corrected or Fredericia-corrected QTc intervals after drug administration on days 1 and 3.
Pharmacokinetics
Plasma palonosetron concentrations declined in a biphasic manner, with an initial rapid distribution phase followed by a slower elimination phase (Figure 2). Palonosetron was measurable in plasma up to 168 hours after day 3 administration in the majority of subjects. Mean values for pharmacokinetic parameters on days 1 and 3 are presented in Table I. On days 1 and 3, the observed mean Cmax values were 1130 and 2430 ng/L, respectively, with coefficients of variation (CV) of 61% and 47%. On day 2, the average concentration 1-minute postdosing was 1620 ng/L with CV of 138%. The observed median Tmax value was 3 minutes after both day 1 and day 3 IV bolus administration of palonosetron. In the majority of subjects, Tmax was observed within 6 minutes after dosing. However, in 1 subject on day 1, Tmax occurred at 2 hours, and in another subject on days 1 and 3, Tmax occurred at 4 hours and 2 hours after dosing. Mean AUC0-24 values were 8900 and 18 200 ng•h/L on day 1 and day 3, with a CV of 22% and 19%, respectively. Mean t1/2 determined after dosing on day 3 was 42.8 hours with a CV of 25%. The intersubject variability of both AUC values and t1/2 values was low. Comparison of AUC values over the same 0- to 24-hour dosing interval following dosing on day 3 relative to dosing on day 1 indicated a mean accumulation ratio of 2.1, consistent with the long t1/2 of palonosetron. Metabolite M9 levels were low and near the limit of quantification; therefore, no pharmacokinetic analysis could be performed for the metabolite.
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Plasma concentration (Cp) time data from a previously studied single 10-µg/kg IV dose administration of palonosetron3 were fitted to a 2-compartment body model with elimination from the central compartment15 to the Cp = Ae-
t + Be-ßt equation, where A and B are coefficients and and ß are distribution and elimination rate constants, respectively.
The estimated parameters, the apparent volume of distribution of the central compartment (Vc [15.3 L]), the first-order elimination rate constant from the central compartment (k10 [0.623 h-1], and the intercompartmental transfer rate constants (k12 [40.1 h-1] and k21 [1.38 h-1]) were used to simulate the plasma concentration time profiles after repeated daily IV dosing of palonosetron. As shown in Figure 3, the model-predicted and the observed mean plasma concentration data from daily dosing for 3 consecutive days of palonosetron are in good agreement, indicating linearity and consistency of the pharmacokinetics of palonosetron with previously published results.3
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The mean plasma concentration of palonosetron in female subjects was consistently higher than in men. This was most likely a result of female subjects receiving higher doses than men did based on body weight (approximately 64 kg for women and 73 kg for men), as a fixed dose of 0.25 mg was administered to all subjects. As shown in Table I, the ratios of female to male Cmax and AUC0-24 parameters on day 1 were 147% (90% CI, 75.9%-284%) and 131% (90% CI, 109%-158%), respectively. On day 3, these ratios were 129% (90% CI, 68.5%-243%) and 118% (90% CI, 97.2%-144%), respectively. The t1/2 of palonosetron in male and female subjects was similar (P = .878), with mean values of 42.3 and 43.3 hours, respectively. Comparison of daily exposure (AUC0-24) on day 3 to day 1 revealed mean accumulation ratios for men and women of 2.21 and 1.98, respectively, which were not statistically different (P = .385).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The pharmacokinetics of palonosetron in this study was similar to that observed in previous single-dose studies of palonosetron in healthy subjects and in cancer patients.2,3 Because palonosetron has a significantly longer plasma elimination half-life than other 5-HT3 receptor antagonists (approximately 40 hours vs 4 to 8 hours),5-7 drug accumulation is likely to occur with repeated dosing, as shown by simulation of plasma concentrations in Figure 3. This was confirmed in the current study, as daily administration of palonosetron 0.25 mg for 3 days resulted in a 2.1-fold accumulation of the drug in plasma. Even with the accumulation of drug in plasma after 3 consecutive daily doses, the observed maximum plasma concentration after the third dose remained lower than the maximum concentrations previously observed in healthy subjects and cancer patients after a single IV 0.75-mg bolus dose of palonosetron.2,3
For metabolite M9, pharmacokinetic analyses could not be conducted, as plasma concentrations were near the lower limit of quantification at most times. The metabolite M9 has been shown to possess less than 1% of the 5-HT3 antagonist activity of palonosetron in isolated guinea pig ileum model. Therefore, coupled with low systemic exposure, the contribution of metabolite M9 to the clinical activity of palonosetron may not be relevant.
There were minor differences in some pharmacokinetic parameters between men and women. For example, women had slightly higher Cmax and AUC0-24, presumably because a fixed dose was administered to all subjects, irrespective of body weight. Because palonosetron has been well tolerated at doses from 3 to 30 times higher than those administered in this study,2,10,11 these slight between-gender pharmacokinetic differences are not expected to be clinically meaningful. Men and women did not differ significantly with respect to palonosetron plasma elimination half-life (42.3 hours and 43.3 hours, respectively) and mean accumulation ratio (2.21 and 1.98, respectively).
Multiple-day dosing of palonosetron 0.25 mg administered as a single, fixed, IV bolus over 3 consecutive days was safe and well tolerated in healthy subjects. Upon repeated dosing, accumulation of palonosetron in plasma was predictable based on its long plasma elimination half-life of 42.8 hours and linear pharmacokinetics. After 3 consecutive daily doses of 0.25 mg, the maximum observed plasma concentration remained lower than the Cmax observed previously in healthy subjects or cancer patients after a single IV 0.75-mg bolus dose of palonosetron,2,3 a dose proven in large, well-controlled phase III clinical trials to be effective, safe, and well-tolerated.10,11 Patients receiving multiple-day chemotherapy regimens are at risk of having acute and delayed nausea and vomiting and may need to be administered antiemetics on multiple days during their chemotherapy.13,14 As a unique 5-HT3 receptor antagonist with extended activity, palonosetron could be particularly useful for patients receiving chemotherapy with emetogenic risk lasting for 4 days or longer; however, safety and efficacy of repeated dosing with palonosetron within a 7-day interval has yet to be evaluated. The results of this study support future investigation into the safety and efficacy of repeated palonosetron dosing in patients with cancer who require preventative antiemetic therapy during multiple-day chemotherapy.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Aloxi [product information]. Bloomington, MN: MGI PHARMA, INC; 2003.
2. Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A. Efficacy, safety, and pharmacokinetics of palonosetron in patients receiving highly emetogenic, cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004;15: 330-337.
3. Stoltz R, Cyong JC, Shah A, Parisi S. Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in US and Japanese healthy subjects. J Clin Pharmacol. 2004;44: 520-531.
4. Stoltz R, Parisi S, Shah A, Macciocchi A. Pharmacokinetics, metabolism and excretion of intravenous [14C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004;25: 329-337.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Anzemet Injection [product information]. Bridgewater, NJ: Aventis Pharmaceuticals; 2003.
6. Kytril [product information]. Nutley, NJ: Roche Laboratories; 2002.
7. Zofran [product information]. Research Triangle Park, NC: GlaxoSmithKline; 2002.
8. Wong EH, Clark R, Leung E, et al. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol. 1995;114: 851-859.[Web of Science][Medline] [Order article via Infotrieve]
9. Miller RC, Galvan M, Gittos MW, van Giersbergen PL, Moser PC, Fozard JR. Pharmacological properties of dolasetron, a potent and selective antagonist at 5-HT3 receptors. Drug Dev Res. 1993;28: 87-93.
10. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al, for the 99-04 Palonosetron Study Group. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial vs dolasetron. Cancer. 2003;98: 2473-2482.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Gralla R, Lichinitser M, Van der Vegt S, et al: Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14: 1570-1577.
12. Aapro MS, Bertoli L, Lordick F, Bogdanova NV, Macciocchi A: Palonosetron (PALO) is effective in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC) [abstract]. Supp Care Cancer. 2003;11: 391. Abstract A-17.
13. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: antiemesis v.1.2004. American Cancer Society. Available at: www.nccn.org/physician_gls/PDF/antiemesis.pdf. Accessed July 26, 2004.
14. Multinational Association for Supportive Care in Cancer: Perugia International Cancer Conference VII—Consensus Conference on Antiemetic Therapy. Perugia 2004 antiemetic guidelines [online]. Available at: http://www.mascc.org/files/MASCC_guideslides060804-1st_ed.pps. Accessed July 26, 2004.
15. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982: 45-111.
16. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest. 2000;18: 163-173.[Web of Science][Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) measured in healthy subjects.