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Single-dose relative bioavailability of a new quetiapine fumarate extended-release formulation: a postprandial, randomized, open-label, two-period crossover study in healthy uruguayan volunteersClinical Therapeutics/Volume 33, Number 6, 2011
Single-Dose Relative Bioavailability of a New Quetiapine
Fumarate Extended-Release Formulation: A Postprandial,
Randomized, Open-Label, Two-Period Crossover Study in
Healthy Uruguayan Volunteers
Francisco E. Estevez-Carrizo, MD1,2; Susana Parrillo, MD1,2;Mónica Cedres Ercoli, PharmD1; and Francisco T. Estevez-Parrillo, BM1 1Center for Clinical Pharmacology Research, Bdbeq S.A., Montevideo, Uruguay; and 2Center forBiomedical Sciences, University of Montevideo, Montevideo, Uruguay ABSTRACT
height, 1.69 [0.09] m; body mass index, 23.7 [3.2] Background: Quetiapine is a dibenzothiazepine de-
kg/m2). Arithmetic mean (SD) of AUC0–36, AUC0–ϱ, rivative that has been established as an effective ther- Cmax, and Tmax were 3279 (1169) ng/mL/h, 3731 apy for schizophrenia and bipolar disorder. A new ex- (1332) ng/mL/h, 341.5 (108.3) ng/mL, and (median tended-release (XR) solid formulation of quetiapine [range]) 5.0 (1.5–12.0) hours, respectively, for the test was developed in the United Kingdom and a Uru- formulation and 3528 (1308) ng/mL/h, 3546 (1350) guayan company has developed a branded generic ver- ng/mL/h, 365.9 (136.4) ng/mL, and (median [range]) 5.0 (2.5–10.0) hours, respectively, for the reference Objective: The goal of the present study was to as-
formulation. The geometric mean (90% CI) for the sess the relative bioavailability of a new XR formula- test/reference ratio of the log-transformed AUC0–36, tion of quetiapine 300 mg versus the XR reference AUC0–ϱ, and Cmax values were: 0.99 (0.91–1.07), 1.06 product after the administration of a high-fat breakfast (0.95–1.18), and 0.94 (0.84 –1.05), respectively. The as required to assume bioequivalence according to the frequency of reported adverse events was: hypotension (27%), dry mouth (27%), dizziness (10%), headache Methods: This was a randomized-sequence, open-
(7%), and nausea (7%). The difference between for-mulations was not statistically significant (P Ͼ 0.05).
label, 2-period crossover study performed in healthy Conclusions: This single-dose study found that the
Uruguayan volunteers with a washout period of 7 test and reference formulations of quetiapine met the reg- days. One tablet of quetiapine XR 300 mg (test and ulatory criteria for bioequivalence among healthy male reference formulations) was administered as a single and female volunteers who took the medicines after a oral dose, and blood samples were collected over 36 high-fat breakfast. Both products were generally well hours. Plasma quetiapine concentration was measured tolerated. (Clin Ther. 2011;33:738 –745) 2011 by using HPLC. Plasma concentration–time curves Elsevier HS Journals, Inc. All rights reserved.
were plotted for each volunteer, and AUC from 0 to 36 Key words: bioequivalence, bipolar disorder phar-
hours (AUC0–36), AUC0–ϱ, Cmax, and Tmax were cal- macokinetics, quetiapine XR, schizophrenia.
culated. A priori bioequivalence requirements were setto require a 90% CI of the test/reference ratios forAUC and Cmax values that were between 0.80 and INTRODUCTION
1.25. Adverse events were determined using clinical Quetiapine, a dibenzothiazepine derivative, is an atyp- assessment, laboratory test results, and monitoring of ical antipsychotic agent indicated for acute and main- vital signs throughout the study. Study subjects were asked to report any adverse events at any time duringthe study.
Accepted for publication May 3, 2011. Results: Twenty-four healthy volunteers (12 men,
12 women) were enrolled and completed the study (mean [SD] age, 31 [6.5] years; weight, 68  kg; 2011 Elsevier HS Journals, Inc. All rights reserved.
Volume 33 Number 6
F.E. Estevez-Carrizo et al.
The mechanism of action is mediated through a an Uruguayan company. Current regulation in Uru- combination of dopamine type 2 and serotonin type 2 guay requires 2 in vivo bioequivalence studies (1 fast- ing and 1 after a high-fat meal) to be filed with the 2) receptor antagonism. The antidepressant activ- ity of is mediated, at least in part, by its marketing authorization dossier of a modified-release metabolite N-desalkylquetiapine through selective Only the bioequivalence study for adminis- norepinephrine reuptake inhibition and 5-HT tration after a high-fat breakfast is presented here.
The present study was designed by the Center for Pharmacokinetic studies of immediate-release (IR) Clinical Pharmacology Research, Bdbeq S.A. (Monte- quetiapine in humans reported that the drug was rap- video, Uruguay) in accordance with the manufacturer idly absorbed after oral administration, with T and reviewed by the Uruguayan regulatory agency.
ues ranging from 1 to 2 hours. Food has been shown to The study was conducted to assess the bioequivalence affect absorption of quetiapine IR tablets (C between the test product* (lot number: 1290309) and the reference product† (lot number: GA081) after a Single- and multiple-dose studies have demon- high-fat, high-calorie breakfast in healthy Uruguayan strated linear pharmacokinetics in the clinical dose range, and elimination is carried out primarily by he-patic metabolism, with a mean terminal t SUBJECTS AND METHODS
Quetiapine is predominantly metabolized by Study Subjects
cytochrome P450 3A4. After administration of 14Cque- The study sample size was calculated under the fol- tiapine, 73% of the radioactivity was excreted in the lowing assumptions: powered between 0.80 and 0.90, urine and 21% in the feces. The parent drug accounted an acceptance range of 0.80 to 1.25, an expected range for Ͻ1% of the excreted radioactivity, and 11 metab- to include the geometric mean of the test/reference ra- olites formed through hepatic oxidation have been tio of 0.95 to 1.05, an ␣ of 0.05, and a within-subject identified. The principal active metabolite is N-desal- %CV of 20%. The result was ϳ24 subjects based on kylquetiapine, which represents about half of the AUC observed for N-desalkylquetiapine wasfound to be a potent norepinephrine reuptake inhibitor Inclusion and Exclusion Criteria
Inclusion criteria were: white women and men aged quetiapine do not appear to be altered by cigarette between 18 and 50 years, body mass index between smoking, because this xenobiotic is not known to af- 18.0 and 30.0 kg/m2, healthy, willing, and with the mental ability to understand and sign an informed con- The following characteristics were found in patients sent form approved by the ethics committee. Results of with schizophrenia or bipolar disorder treated with all laboratory tests had to be within the reference range 300 mg of extended-release (XR) quetiapine fumarate for the hospital clinical laboratory.
or 150 mg of IR quetiapine fumarate BID: C Exclusion criteria were: participation in another steady state, 495 versus 568 ng/mL (difference, 13%); clinical study, blood donation or blood loss within 6 months of the inception of the study, history of alcohol max, 5 versus 2 hours; and Cmin, 95.3 versus 96.5 ng/mL, respectively. These findings suggest that the or drug abuse, smoking Ͼ10 cigarettes per day, allergic pharmacokinetic performance of the once-daily que- diathesis, allergy to drugs, systolic blood pressure Ͻ65 tiapine XR formulation is similar to the IR BID formu- mm Hg and/or diastolic blood pressure Ͼ140 mm Hg, lation, supporting the use of quetiapine XR as a once- heart rate outside the range of 60 to 90 beats/min, body temperature outside the range of 36.4°C to 37.1°C, An XR formulation of quetiapine was developed by any clinically significant acute disease within the last 4 a pharmaceutical company in the United Kingdom to weeks, any chronic disease, ingestion of any systemic provide more convenient once-daily administration, aswell as allowing simple and rapid dose escalation; the *Trademark: Quetia® XR 300 mg (Laboratorios Gautier, Mon- goal was to improve compliance, which is a substantial †Trademark: Seroquel® XR 300 mg (AstraZeneca, Macclesfield, XR solid formulation of quetiapine was developed by June 2011
drug within 2 months before the study, or ingestion of 2 hours after drug administration (except for the water any drug-metabolizing enzyme inductor or inhibitor (food or xenobiotic) within the last 21 days. Women Body temperature, blood pressure, and heart rate were committed to using contraceptive methods in or- were monitored 2, 4, 8, 12, 24, and 36 hours after der to avoid pregnancy during the study, and up to 2 quetiapine administration. Body temperature was weeks after the second administration. A blood measured with a thermocouple meter in the armpit, ␤-HCG test was performed immediately before drug blood pressure was measured with an aneroid sphyg- momanometer in the right arm (if the vein cannula isin the right arm then blood pressure was measured inthe left arm), and heart rate was measured manually Study Design and Clinical Protocol
on the radial artery. Hypotension was defined as This was a randomized-sequence, single-dose, post- diastolic blood pressure Ͻ65 mm Hg and/or systolic prandial, 2-period crossover study with a washout pe- riod of 1 week. The design was open-label, according Subjects were closely supervised for orthostatic hy- potension and/or syncope (abrupt and transitory fall- protocol was reviewed and accepted by the Human ing and unconsciousness) at all times and specifically to Research Ethics Committee of the Catholic University 1, 2, 4, 6, 8, 10, 12, 24, and 36 hours after ingestion of of Uruguay (number: A.04.11.09) on November 19, the XR formulation. Orthostatic hypotension was de- 2009. The details and purpose of the study were care- termined as follows: blood pressure was measured in fully explained in plain language to all volunteers. All the right arm with the subject lying down (dorsal de- subjects participating provided written informed con- cubitus) on the bed; the subject was asked to stand sent before subject screening. Subject numbers and erect by the bed, and blood pressure was measured their sequences were computed with a random number again in the same arm. After this procedure, hypoten- generator (SPSS 15.0; SPSS Inc., Chicago, Illinois) to sion was verified according to the following criteria: assign patients to either sequence (test–reference or diastolic blood pressure Ͻ65 mm Hg and/or systolic blood pressure Ͻ95 mm Hg measured 3 minutes after During each period, the subjects were admitted to the Center for Clinical Pharmacology Research at the After a 1-week washout period, subjects were crossed Italian Hospital (Montevideo City, Uruguay) the eve- over and all procedures were repeated. All subjects had ning before the study day at 8:00 PM and had dinner their physical examinations and laboratory analysis con- before 10:00 PM. The next morning, subjects consumed ducted 1 week after completion of period 2.
a high-calorie breakfast (1000 kcal; 50% fat, 35% car-bohydrates, and 15% protein). An example of thisbreakfast is as follows: a sandwich prepared with two Blood Sampling
100-mg slices of wheat bread spread with 50 mg of The duration of sampling period was approximately butter and two 25-mg slices of ham, a 250-mg sweet 5 elimination t1/2 for quetiapine (36 hours), and the muffin, and 250 mL of whole milk with decaffeinated washout period was 7 days. Ten-milliliter blood sam- coffee. Within 15 minutes of finishing the meal, sub- ples were collected into polypropylene tubes with 50 jects took a single 300-mg quetiapine XR tablet with L of sodium heparin solution (50 IU/mL) at room 250 mL of tap water at room temperature. Volunteers temperature by catheterized venipuncture in the sub- stayed in bed and were closely supervised for 10 hours ject’s forearm. One milliliter of blood was discarded after drug intake. After that time, subjects were care- before sampling and, after collecting the sample, the fully controlled for orthostatic hypotension before get- catheter was flushed with 1 mL of sodium heparin sa- line solution (50 IU/mL). Samples were drawn 6 min- For each study period, a lunch (ϳ800 kcal) was utes before administration and 0.5, 1, 1.5, 2, 2.5, 3, 4, provided 4 hours after study drug administration, a 5, 6, 8, 10, 12, 18, 24, and 36 hours after administra- snack (ϳ200 kcal) after 8 hours, a dinner (ϳ600 kcal) tion. The blood samples were centrifuged at 4°C in a after 12 hours, and a breakfast (300 kcal) after 24 refrigerated bench-top centrifuge with relative centrif- hours. Water was allowed except for 1 hour before and ugal force of 1500g for 10 minutes. Plasma samples Volume 33 Number 6
F.E. Estevez-Carrizo et al.
were stored in glass tubes at –20°C for subsequent trol (480 ng/mL), respectively. The recovery for the internal standard was 88.0% at a concentration of 50g/mL.
Determination of Quetiapine Plasma
The values of low, medium, and high quality control Concentrations
were between 97.3% and 103.2% in both intraday and interday accuracy. The intraday relative SD was be- tracted plasma samples was validated according to the tween 1.8% and 4.2%, and the interday relative SD US Food and Drug Administration guidelines for bio- analytical method Validation and mea-suring of samples were conducted at the Bio-analytical Adverse Events
Unit of the Center for Clinical Pharmacology Re- Adverse events were determined using clinical as- sessment, monitoring of vital signs (blood pressure, Quetiapine fumarate was provided by Laboratorio heart rate, and body temperature), and interrogation Gautier Uruguay (Montevideo, Uruguay). Lamotrigine of volunteers by a blinded operator on a prewritten (internal standard) was obtained from Sigma Chemical questionnaire at baseline, during hospitalization, dur- Company (St. Louis, Missouri). All other chemicals ing ambulatory visits, and at the end of the clinical were analytical and/or HPLC grade. Photodiode array stage of the study. Laboratory results were also consid- with internal standard (Waters 2996 PDA; Waters ered. Life-threatening adverse events that led to death, Corporation, Milford, Massachusetts) was used for hospitalization, disability, and/or medical intervention to prevent permanent impairment or damage were Briefly, the clean-up procedure for the extraction of quetiapine from the biological matrix consisted ofsolid-phase extraction. The sample (1.0 mL, humanplasma) and the internal standard (25 L, lamotrigine Pharmacokinetic and Statistical Analyses
50 g/mL) was loaded on C2 cartridges 1 cc, 100 mg Individual plasma concentration–time profiles for (Waters), and washed twice with 250 L of water. The each volunteer and mean values for each sampling time cartridges were eluted with 250 L of methanol. The were plotted. AUC0–36 was calculated using the linear eluates were diluted with 250 L of mobile phase and trapezoidal method; Cmax, and Tmax were obtained di- injected (100 L) into the HPLC system (Waters 717 rectly from the concentration–time curves; ke was cal- plus Autosampler; Waters Corporation). The chro- culated applying a log-linear regression analysis; and matographic separation was conducted on a C18 col- umn (250 mm ϫ 4.6 mm; particle size of 5 m; Thermo Scientific BDS Hypersil [Thermo Fisher Scien- ANOVA was performed on log-transformed values tific Inc., New York, New York]) fitted with C18 secu- of the pharmacokinetic characteristics AUC0–36, rity guard cartridges. The mobile phase was a mixture AUC0–ϱ, and Cmax using SPSS 15.01 (SPSS Inc.). The of 40-mM phosphate buffer (pH 1.9), acetonitrile, and ANOVA model included product, sequence, and pe- methanol in a ratio of 82:13:5 vol/vol. All separations riod as fixed effects and subject nested within sequence were performed isocratically at a flow rate of 1.0 mL/ as a random These effects were tested at the min, and the column was maintained at 45°C.
statistical significance level of ␣ ϭ 0.05.
Quetiapine and the internal standard were mea- To claim bioequivalence between the products sured in a Waters 2996 PDA UV-visible detector oper- based on local regulatory requirements, the 90% CIs ated at a wavelength of 257.0 nm. The calibration for the ratios of AUC0–36, AUC0–ϱ, and Cmax for the curves were linear in the range of 20 to 600 ng/mL, test and reference products using log-transformed data with a determination coefficient (of 0.999. The limit were calculated. The test and reference formulations of quantitation of this method was found to be 20 were considered bioequivalent if the 90% CIs for the ng/mL for quetiapine (relative SD, 8.0% [nϭ8]). The characteristics evaluated fell within the range of 0.80 absolute recoveries were 80.0%, 89.0%, and 95.0% for quetiapine at low quality control (60 ng/mL), mid- (Wilcoxon signed rank test) was applied to compare dle quality control (205 ng/mL), and high quality con- June 2011
concentration–time curves for each volunteer accord-ing to formulation is shown in provides a description of the pharmacoki- netic characteristics for both formulations. The %CV is shown for all the pharmacokinetic parameters, whereas the within-subject %CV is shown only for the evaluable parameters. ANOVA analysis (general linear modeling, SAS 9.1) revealed that the formulation effect did not attain the level of statistical significance with regard to AUC0–36, AUC0–ϱ, and Cmax. Furthermore, no significant subject, subject-within-sequence, or pe- riod effect was found for these pharmacokinetic Figure 1. Mean concentration–time curves for 24 The 90% CIs for the test/reference ratio of the log- transformed AUC0–36, AUC0–ϱ, and Cmax values are of 300 mg of quetiapine as the test for-mulation (Quetia® XR 300 mg [Labora-torios Gautier, Montevideo, Uruguay])or the reference formulation (Seroquel® RESULTS
Twenty-four healthy Uruguayan volunteers (12 men,
12 women) completed the study. Demographic charac- teristics (mean [SD]) were as follows: age, 31 (6.5) years; weight, 68 (12) kg; height, 1.69 (0.09) m; body mass index, 23.7 (3.2) kg/m2. The results of physical examination of the 24 subjects during prestudy and poststudy visits were normal. All subjects were free from significant cardiac, hepatic, renal, gastrointesti- nal, hematologic, endocrine, and immunologic dis- eases as assessed by physical examination and clinical laboratory test results. No volunteer was withdrawn All laboratory analyses were performed by the hospital clinical laboratory (Biofast, Montevideo, Uruguay), which has been authorized by the local health authority to provide services to the Center forClinical Pharmacology Research. Biofast is certified Figure 2. (A) Overlay plot of concentration–time by the Quality Program of the Sociedade Brasileira curves for each of the 24 volunteers afteradministration of the test formulation de Patología Clinica e Medicina Laboratorial tier, Montevideo, Uruguay]); or (B) afteradministration of the reference formula- Bioequivalence of Quetiapine XR
Mean plasma concentration–time curves of quetia- eca, Macclesfield, Cheshire, United King- pine after a single dose of either 300-mg tablet formu- lation are plotted in The overlay plot of the Volume 33 Number 6
F.E. Estevez-Carrizo et al.
Table I. Pharmacokinetic characteristics and variability of both quetiapine products tested.
ϭ AUC from 0 to 36 hours; k ϭ absorption rate constant.
*Trademark: Quetia® XR 300 mg (Laboratorios Gautier, Montevideo, Uruguay).
†Trademark: Seroquel® XR 300 mg (AstraZeneca, Macclesfield, Cheshire, United Kingdom).
shown in The difference in Tmax values be- was reported. One subject was not compliant with the tween the 2 products was not statistically significantly protocol by standing up out of bed without calling the different, according to the Wilcoxon signed rank test nurse. He experienced syncope but regained conscious- Adverse Events
Table III. Incidence of adverse events reported Twelve participants reported a total of 30 adverse events, 15 with the test product and 15 with the refer-ence product. The most frequently reported adverse events were hypotension (orthostatic and asymptom- atic; 27%), dry mouth (27%), dizziness (10%), head- Formulation*
ache (7%), and nausea (7%) Sedation andsleep occurred in all participants. One case of vomiting *Trademark: Quetia® XR 300 mg (Laboratorios Gautier, Mon- Trademark: Seroquel® XR 300 mg (AstraZeneca, Macclesfield, June 2011
ness immediately, and his blood pressured recovered to explain the low incidence of this known adverse effect pretreatment values within 10 minutes of the inception of quetiapine compared with the results of other au- of the episode. An ECG performed within 5 minutes of The only study participant with syncope re- the episode did not show any arrhythmia or heart portedly regained consciousness and recovered from hypotension immediately with physical maneuvers. No All adverse events were mild or moderate in inten- arrhythmias were detected in this volunteer. Other ad- sity (no serious or unexpected adverse events occurred) verse effects (eg, dry mouth, headache, dizziness) were and were imputed as “likely” in a scale of relatedness mild, transient, and improved without therapeutic to therapy (Not related, Unlikely, Possible, Likely, Cer- tain, Not assessable). All adverse events were transient;improved with observation, physical measures, or CONCLUSIONS
symptomatic medication; and were not related to que- This single-dose study found that the test and reference products of quetiapine met the regulatory criteria forbioequivalence among healthy male and female volun- DISCUSSION
teers who received medications after a high-fat break- Quetiapine ER has been successfully used in patients fast. Elimination t1/2 was somewhat longer for the test with schizophrenia, bipolar disorder, and major de- product. Both products were generally well tolerated pressive disorder with once-daily administration, even though sedation occurred in all participants and showing long-term symptomatic remission, safety, hypotension was detected in more than one quarter of study suggests that the test formulation can be as-sumed bioequivalent with the test formulation, as ACKNOWLEDGMENTS
defined by Uruguayan regulations. However, it has The authors wish to thank Professor C. Daniel Mull- some noteworthy limitations, namely that it was a ins, PhD, for the final revision of this manuscript as single-dose study among young, healthy volunteers; well as Q.F. Delia Muxi and Q.F. Alexis Arana for therefore, pharmacokinetic and safety conclusions providing the investigational drug and analytic stan- cannot be generalized beyond the conditions and dards. This study was supported by Laboratorios Gau- tier. The sponsor was not involved in the design, con- Another limitation of the study is the highly variable duct, or analysis of the study. The authors have kinetic disposition between subjects and formulations.
indicated that they have no conflicts of interest regard- e of both products, the variability could be due to differences in galenic modifications that affect therate of absorption. Conversely, absorption (dissolu- REFERENCES
tion) of quetiapine from the test formulation might 1. Peuskens J, Trivedy JK , Brecher M, Miller F. Long-term have a stronger rate-limiting effect than from the symptomatic remission of schizophrenia with once-daily reference formulation, explaining the difference in extended release quetiapine fumarate: post-hoc analysis of ke. Adverse-event profiles were similar for both data from a randomized withdrawal, placebo-controlled products. Sedation, somnolence, and sleep occurred study. Int Clin Psychopharmacol. 2010;25:183–187.
in all the volunteers. The effect accrued slowly dur- 2. Meulien D, Huizar K, Brechner M. Safety and tolerability of ing the first hours postadministration; however, af- once-daily extended release quetiapine fumarate in acute ter hours 2 and 3, all volunteers were sleeping. These schizophrenia: pooled data from randomized, double- results are consistent with those reported by Mahat- blind, placebo-controlled studies. Hum Psychopharmacol.
thanatrakul et in quetiapine IR and by Datto et 3. Al Jurdi RK, Dixit LA, Satajovic M. Role of extended release quetiapine in the management of bipolar disorders. Neuro- Hypotension explains more than one quarter of the psychiatr Dis Treat. 2010;6:29 –35.
reported adverse events, and only a few of these events 4. McIntyre RS, Muzina DJ, Adams A, et al. Quetiapine XR proved to be orthostatic hypotension. The fact that efficacy and tolerability as monotherapy and as adjunctive subjects stayed in bed for most of the day and were treatment to conventional antidepressants in the acute and closely supervised when they did rise out of bed might maintenance treatment of major depressive disorder: a review Volume 33 Number 6
F.E. Estevez-Carrizo et al.
of registration trials. Expert Opin Phar- macother. 2009;10:3061–3075.
14. Diletti E, Hauschke D, Steinijans W.
Wiley & Sons, Ltd; 2007:69 –104.
19. Sauter R, Steinijans VW, Diletti E, et confidence intervals. Int J Clin Pharma- equivalence studies. Int J Clin Pharma- col Ther Toxicol. 1992;30(Suppl 1): col Ther Toxicol. 1992;30(Suppl 1): study. J Clin Psychiatry. 2009;70:540 – 15. Guidance for Industry. Bioavailability availability. J Pharmacokinet Biopharm.
21. Guidance for Industry. Statistical Ap- antidepressant activity. Neuropsychop- harmacology. 2008;33:2303–2312.
atypical antipsychotic. Clin Pharmaco- 16. Hasselstrøm J, Linnet K. Fully auto- tography. J Chromatogr B Analyt Tech- nol Biomed Life Sci. 2003;798:9 –16.
healthy male volunteers. Int J Clin Pharmacol Ther. 2008;46:489 – 496.
23. Datto C, Berggren L, Patel JB, Eriksson Met Disp. 2009;37:254 –258.
jects. Clin Ther. 2009;31:492–502.
kinetic profiles of extended releasequetiapine fumarate compared withquetiapine immediate release. ProgNeuropsychopharmacol Biol Psychiatry.
extended release: in schizophrenia.
CNS Drugs. 2009;23:261–269.
realización de estudios de bioequiva-lencia. Anexos, I, II y III. DecretoN° 12/2007, Ministerio de Salud Address correspondence to: Francisco E. Estevez-Carrizo, MD, Center for
Clinical Pharmacology Research, Bdbeq S.A., Hospital Italiano, Br. Artigas 1632, CP 11600 Montevideo, Uruguay. E-mail: June 2011
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