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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan (Dr. Tashiro, Dr. Sakurada, Dr. Iwabuchi, Dr. Mochizuki, M. Kato, M. Aoki, Dr. Yanai); the Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan (Dr. Funaki, Dr. Itoh, Dr. Iwata); and the Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr. Wong).
Address for reprints: Professor Kazuhiko Yanai, Department of Pharmacology, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Fexofenadine • cetirizine • histamine H1-receptor (H1R) • sleepiness • psychomotor performance • positron emission tomography (PET) • second-generation antihistamine • H1-receptor occupancy (H1RO)
Numerous studies have used various performance tests to compare the sedative profiles of first- and second-generation antihistamines.8-16 However, as a result of limited sensitivity, similar comparisons between different second-generation antihistamines using psychomotor testing may be more difficult. A recent meta-analysis using proportional impairment ratios (PIRs) to compare different antihistamines has indicated that fexofenadine was the least sedative of all the antihistamines studied, whereas cetirizine was categorized as being slightly sedative.29,30 This calculation is valuable, especially in the comparison of second-generation antihistamines; however, it requires a large amount of research and reviewing of all previously reported measurements. Therefore, a more direct measurement would be of benefit.
It is known that the unfavorable side effects of antihistamines are caused by blocking nerve transmission of the histaminergic neuron system, which projects from the tuberomammillary nucleus to almost all cortical and subcortical structures. Those antihistamines that easily penetrate the BBB occupy a large proportion of postsynaptic H1Rs, and variations in the cerebral H1R occupancies (H1RO) of antihistamines may be a result of their different BBB permeabilities; H1RO can be evaluated using positron emission tomography (PET), a noninvasive functional neuroimaging technique.31-36 PET has been widely used for drug development and the evaluation of drug effects using various radioactive tracers.37-41 By using 11C-doxepin, a tracer that specifically binds to H1Rs, it is also possible to calculate H1RO.31-36 This technique has proved a reliable way of determining the sedative index of an antihistamine.31-36
The primary aim of the present study was to compare the sensitivities of 3 measuring methods—subjective sleepiness assessments, psychomotor testing, and PET imaging—in a differential comparison of the sedative profiles of fexofenadine and cetirizine, 2 different second-generation antihistamines. In addition, the secondary aim of the present study was to evaluate the sedative profiles of fexofenadine and cetirizine, based on recent criteria from the Consensus Group on New Generation Antihistamines (CONGA), which recommended measuring subjective sleepiness, psychomotor testing, and H1RO measured by PET as indices of sedative profiles of antihistamines.42
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects
Twenty healthy male Japanese volunteers (mean age ± SD: 23.2 ± 2.7 years; mean weight 67.2 ± 13.7 kg) were recruited for cognitive tests to examine the sedative effects of fexofenadine and cetirizine. Eleven of the 20 subjects (mean age ± SD: 23.2 ± 2.7 years; mean weight 67.1 kg) underwent 2 PET measurements to determine the H1R binding of 11C-doxepin after oral administration of fexofenadine and cetirizine. An additional 11 age-matched male volunteers (mean age ± SD: 22.6 ± 1.1 years; mean weight 65.9 ± 11.6 kg) were recruited to determine the baseline value of 11C-doxepin binding to H1R as described in our previous reports.31,32,33 Ideally, the same subjects should be scanned 3 times for fexofenadine, cetirizine, and placebo conditions to minimize the effect of intersubject variability in the baseline value of binding. However, because of limitations on radiation exposure, we obtained the baseline data from different subjects. Only 1 subject of the 20 who also underwent the cognitive study had 3 PET measurements to determine the H1R binding of 11C-doxepin after oral administration of fexofenadine, cetirizine, and placebo with a high sensitivity scanner.
Written informed consent was obtained from all subjects before undergoing the study. All subjects were in good health without a significant clinical history of physical and mental illness and were not receiving any concomitant medication likely to interfere with the study results. Alcohol, nicotine, caffeine, grapefruit, and grapefruit juice were forbidden during the study, and food intake was controlled.
Study Design
Subjects (n = 20) underwent psychomotor tasks before (baseline) and after single oral doses of fexofenadine 120 mg, cetirizine 20 mg, lactobacteria preparation 12 mg (placebo), and hydroxyzine 30 mg (positive control) in a double-blind, randomized, 4-way crossover study, with minimum washout intervals of 6 days between treatments. The doses of fexofenadine and cetirizine administered were double the single recommended doses (the maximum allowable daily dosages) in Japan at the time of the study. This was to enable the potentially small differences between the 2 second-generation antihistamines to be highlighted. The lactobacteria preparation (Biofermin R) has been widely used as a placebo in Japan, giving no statistical difference pre- and postadministration in previous studies.32-35,41,43
Subjects were trained on each psychomotor task for approximately 10 min, until each subject felt familiar with all tasks, and were asked to have a rest for 2 to 3 min; then, pretreatment baseline measurements were made, with a rest period between each task (approximately 2 min per task). Psychomotor testing was resumed at 90 min posttreatment, corresponding approximately with the tmax of both drugs, with subjects undergoing 3 types of performance assessments: choice reaction time (CRT), simple reaction time (SRT), and visual discrimination task (VDT). Two parameters, reaction time (RT) and accuracy, were obtained for each task.35,43 Subjective sleepiness and alertness were also evaluated using the Stanford Sleepiness Scale (SSS) just prior to the baseline tasks and following psychomotor tasks. The SSS is composed of a 7-level self-report measurement.44 Subjects were instructed to select a specific statement best describing their state of sleepiness (Figure 1).35,43
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Blood samples were obtained just after the cognitive tests at around 120 min postadministration to determine the plasma concentrations of fexofenadine, cetirizine, and hydroxyzine (Figure 1). The method for determining plasma drug concentrations is explained later.
H1RO was measured using PET in a randomized, single-blind crossover study design at 90 min postdose of fexofenadine and cetirizine. This part of the study was single blinded, as the investigators had to report the medication. All 11 subjects were scanned twice following administration of fexofenadine and cetirizine, with at least a 6-day interval between treatments. Only 1 subject was scanned 3 times following administration of fexofenadine, cetirizine, and placebo, with at least a 6-day interval. The present protocol was designed based on an institutional guideline for radiation exposure at the CYRIC, where maximal radiation exposure to a healthy volunteer was recommended as 5 mSv per year and 10 mSv per 5 years. According to a previous report from the CYRIC, averaged exposure to the volunteers (effective doses) due to injected 11C-doxepin was calculated as 6.92 x 10-3 mSv/MBq (or 0.256 mSv/mCi).45 Based on these data and institutional guidelines, 2 scans per subject were planned for 11 subjects with an approximate dose of 300 MBq (approximately 8 mCi) 11C-doxepin per study. It was planned to scan different subjects with the same age and body sizes for baseline value for 11C-doxepin binding.
Blood samples were obtained at 30, 60, 90, 120, 150, and 180 min postadministration to determine the plasma concentrations of fexofenadine and cetirizine. The areas under the curve (AUC) from 0 to 180 min were calculated, and their correlation to H1RO was examined.
Measurement of Cognitive Performance and Subjective Sleepiness
CRT, SRT, and VDT are "attention-dependent" cognitive tasks. In the CRT, subjects were instructed to press a button promptly with their left or right index finger corresponding with the appearance of a visual target (a circle) on either the left- or right-hand side of an AV tachistoscope monitor (IS702, Iwatsu, Inc, Japan). In the SRT, subjects were to press the right-hand button promptly with the right index finger when the visual target appeared, regardless of the positioning of the target. In both tasks, the length of the interval between target displays was randomized to ensure that the tasks remained attention dependent. In the VDT, subjects were instructed to distinguish target stimuli (1-digit Arabic numerals) from nontarget stimuli (Japanese characters) displayed on the AV tachistoscope monitor and to press a button only when the target stimuli were displayed. For the VDT, 4 sessions were repeated with different target exposure durations (3, 5, 7, and 20 msec) in a random order, and the exposure duration of the targets was kept constant in each session. Further details of the cognitive tests have been described previously.35,43 The testing procedure took 
30 min and was completed at 120 min postadministration, at which stage 8 mL of venous blood was collected from each subject for measurement of plasma antihistamine concentration.
PET Measurement of Antihistamine H1RO
Eleven of the 12 PET subjects were administered single oral doses of fexofenadine 120 mg or cetirizine 20 mg and were scanned using an ECAT PT931/04-12 scanner (CTI, Inc, Knoxville, Tenn), and a further 11 subjects were administered placebo and scanned with the same equipment. The ECAT PT931/04-12 scanner has a spatial resolution of 7 to 8 mm FWHM in the center of the field of view (FOV) and has a 5-cm-long axial FOV that is not capable of covering the whole brain.46 Due to institutional guidelines suggested by the reviewing committee, PET measurements with this scanner were not performed more than twice, and therefore different subjects were recruited for obtaining the baseline values of 11C-doxepin binding. Only 1 subject was scanned under the 3 conditions of fexofenadine, cetirizine, and placebo using a SET2400W scanner (Shimadzu, Inc, Japan), which had higher sensitivity. This scanner, with a 20-cm-long axial FOV, enabled the whole brain to be scanned in 1 frame; this has been previously reported in more detail.47 The subject who experienced 3 scans was scanned according to the same protocol as the other subjects.
The subjects were positioned so that transaxial slices were parallel to the orbito-meatal line and underwent a 10-min transmission scan using the 68Ge/68Ga line source for tissue attenuation correction. An emission scan for measurement of binding potentials of 11C-doxepin was started at 90 min postadministration of fexofenadine and cetirizine, corresponding approximately with the tmax of both antihistamines simultaneously to the injection of 11C-doxepin-containing saline solution to the subjects. The scan took a further 90 min for acquisition of dynamic images (22 sequential scans: 6 scans for 90 sec, 7 scans for 180 sec, 6 scans for 300 sec, and 3 scans for 600 sec).
11C-Doxepin was synthesized by an automated system48; the radiochemical and chemical purities of the 11C-labeled ligand were both > 99%. The specific radioactivity at the time of injection was 73.8 ± 52.8 GBq/µmol (1995 ± 1428 mCi/µmol). The injected dose and cold mass per study were 302 ± 122 MBq (8.18 ± 3.30 mCi) and 6.89 ± 6.12 nmol (1.22 ± 1.09 µg), respectively. The averaged radiological dose was approximately 310.8 MBq (or 8.4 mCi) per investigation for the subjects who underwent 1 or 2 scans with the ECAT scanner and 183.6 MBq (or 5.0 mCi) per investigation for the subject who underwent 3 scans with the Shimadzu scanner. The average radiation exposure to subjects who had 1 scan, 2 scans, and 3 scans was 2.16 mSv, 4.31 mSv, and 3.81 mSv, respectively, with all being below the maximal exposure recommended (5 mSv) by the institutional guidelines.
Plasma concentrations of the antihistamines—fexofenadine, cetirizine, and hydroxyzine—were determined with a sensitive method, based on a previous report by Sutherland et al,49 using a high-performance liquid chromatographic (HPLC [LC/MS/MS]) separation with tandem mass-spectrometric detection from the blood samples obtained in the cognitive study (for fexofenadine, cetirizine, and hydroxyzine) and in the PET investigations (for fexofenadine and cetirizine).
The samples were extracted from plasma with toluene, followed by back-extraction into formic acid (2%) for cetirizine, after which the toluene containing the antihistamines was evaporated and the analyte reconstituted and combined with the cetirizine back-extract. Chromatography was performed on a Phenomenex Luna C18 (2) 3-micron, 50 x 2.0-mm column with a mobile phase. The mobile phase consisted of 95% methanol (MeOH) with 1.25 mL ammonium hydroxide and 2.5 mL glacial acetic acid, consisting of acetonitrile/0.1% formic acid using gradient elution (60%-95% MeOH in 2 min, then to 60% MeOH at 3.6 min) at a flow rate of 0.3 mL/min. Detection was achieved using a Perkin-Elmer API 2000 mass spectrometer (LC/MS/MS) set at unit resolution in the multiple-reaction monitoring mode. Turbo-IonSpray ionization was used for ion production.
The samples from the cognitive study were used to examine the correlation of subjective sleepiness, reaction time, and accuracy to the plasma concentration in the cognitive tests. The samples from the PET investigation were used for evaluation of tmax and the association between the binding potential and plasma concentrations.
Image Analysis
After being corrected for tissue attenuation, brain images were processed by applying a graphical analysis to obtain binding potential (BP) images.50,51 The standard arterial time-activity curve was used to calculate parametric brain images of the distribution volume (Vd) of 11C-doxepin. A region of interest (ROI) was defined in the cerebellum of the Vd image as a reference region, and brain BP images were created by subtracting 1.0 from the Vd value of each voxel divided by the cerebellar ROI value. The method was validated and described in more detail in previous publications.32,34 Finally, brain BP images were created from which H1RO was calculated for the prefrontal, cingulate, orbitofrontal, temporal, and occipital cortices, as well as the basal ganglia and thalamus. The H1ROs of fexofenadine and cetirizine were calculated based on the following equation: H1RO = [(mean BP of the control-mean BP with a given antihistamine)/mean BP of control] x 100.32-34
Statistical Analysis
Changes from baseline were calculated for RT and accuracy in the CRT, SRT, and VDT tasks (at 4 different exposure durations for VDT), as well as for subjective sleepiness, by subtracting the values obtained before antihistamine administration from the values obtained after administration. Because some data sets did not display normal distribution and equal variance, the data were tested by nonparametric Friedman's test followed by Bonferroni correction for multiple comparisons to describe the present data set accurately.52 In addition, Spearman's rank correlation test was used to examine the correlation between plasma drug concentration and treatment changes of RT, accuracy, and subjective sleepiness.
The difference in BP between fexofenadine and cetirizine was examined using a Mann-Whitney test. The relationship between plasma drug concentrations and BP values, was examined using Spearman's rank correlation test. A probability of < 0.05 was considered to be statistically significant. The statistical calculations were performed using SPSS for Windows 11.0.1 (Japanese version).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Cognitive Performance: Accuracy
No significant differences were observed between any treatments for SRT and CRT. The change in accuracy after fexofenadine administration was not significantly different from that seen with placebo in all the VDT tasks. The change in accuracy after cetirizine treatment tended to be larger than that after placebo. The change in accuracy from baseline was significantly different between placebo and hydroxyzine for all VDT tasks (3, 5, 7, and 20 msec) (P < .05), showing that the sensitivity of this measurement was high enough (Figure 3).
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The change in accuracy after fexofenadine administration was significantly smaller than that experienced with hydroxyzine in the 3-, 5-, and 20-msec VDT tasks (P 
.01). The change from baseline in accuracy with cetirizine was no different from that seen with hydroxyzine in any of the tests apart from the 5-msec VDT task (P = .037) (Figure 3). The change in accuracy after cetirizine treatment tended to be larger than that after fexofenadine, reaching statistical significance compared with fexofenadine in the 3-msec VDT (P = .02).
Subjective Sleepiness
The change in subjective sleepiness scores was significantly different between placebo and hydroxyzine, as assessed before each psychomotor task (P < .05), whereas the change seen with fexofenadine was not significantly different from that with placebo (data not shown). The change in sleepiness scores with fexofenadine was significantly smaller than that with hydroxyzine at all time points (P < .05), apart from the measurement taken prior to the cognitive tests (pretest).
The change with cetirizine did not differ significantly from that with placebo at any assessment point but was only significantly different compared with that of hydroxyzine in the assessment prior to the third VDT test (VDT2) (P = .023). The change with cetirizine was also significantly greater than that with fexofenadine prior to the fourth VDT test (VDT3) (P < .027) (data not shown).
Antihistamine Plasma Concentrations
Measurements of plasma concentrations of fexofenadine and cetirizine at 0, 30, 60, 90, 120, 150, and 180 min postadministration indicated that Cmax occurred from 60 to 120 min for both agents (Table I).
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No significant correlation was found between fexofenadine plasma concentrations and the results of the psychomotor and sleepiness assessments. For cetirizine, no correlation was found between plasma concentrations and impairment except for weak but significant correlations in 2 measures: accuracy for the 3-msec VDT (P = .04) and for the reaction time for the CRT (P = .035).
For hydroxyzine, a significant correlation was detected for plasma concentration and changes in accuracy (VDT 3, 5, 7, and 20 msec: P = .001, .003, .013, and .002, respectively) and in RT (CRT, SRT, and VDT 3, 5, 7, and 20 msec: P < .001, P < .001, P = .034, P = .001, P < .001, and P = .002, respectively, as well as changes in subjective sleepiness (CRT, SRT, and VDT at 3, 5, 7, and 20 msec: P = .003, P = .007, P = .001, P < .001, P < .001, and P = .002, respectively) (Spearman test) (data not shown).
Antihistamine H1RO
The BP of 11C-doxepin, as measured by PET, was in general higher in the fexofenadine condition than in the cetirizine condition, indicating that fexofenadine had not blocked the H1Rs. Regional 11C-doxepin BP data calculated by ROI analysis were significantly higher with fexofenadine compared with cetirizine in the prefrontal, cingulate, orbitofrontal, and occipital cortices and in the thalamus and basal ganglia (Table II). No significant relationship was detected between regional BP values and plasma drug concentrations both for fexofenadine and cetirizine.
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The H1RO of fexofenadine was lower than that of cetirizine in all brain regions studied (Table II). In addition, in the 1 subject receiving all 3 treatments, the images obtained after fexofenadine treatment were very similar to those obtained after placebo treatment (Figure 4). The images after cetirizine treatment demonstrated lower binding than those after treatments with fexofenadine and placebo (Figure 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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It is well known that first-generation antihistamines such as diphenhydramine, hydroxyzine, promethazine, and chlorpheniramine are highly sedating, creating potentially dangerous problems for patients involved in driving or those operating planes or heavy machinery, even at recommended doses.1-3 Hydroxyzine, the precursor of cetirizine, is a typical first-generation antihistamine that induces psychomotor impairment even at recommended doses (20-30 mg) and has been used as a positive control in a number of studies7,11,12,17 to confirm the sensitivity of the tests. Similarly, other first-generation antihistamines such as promethazine,9,21,23,26 diphenhydramine,8,14,24 triprolidine,10 and chlorpheniramine41 have been used as positive controls.13,16,18,22,25 In comparison, second-generation antihistamines, including fexofenadine, loratadine, and cetirizine, are regarded as being less impairing and sedating and are, therefore, safer to use in day-to-day activities.2,4 However, further investigations have demonstrated that not all second-generation drugs manifest similar "nonsedative" profiles.4
In the present study, the psychomotor tests revealed that fexofenadine 120 mg was not significantly different from placebo for all tasks and significantly less impairing than cetirizine 20 mg for some of the tasks. These results are validated by those obtained with the positive internal control, hydroxyzine, confirming the sensitivity of the study. However, the difference between fexofenadine and cetirizine was significant only for 2 of the 12 cognitive measurements (changes in reaction time for CRT and accuracy for 3-msec VDT), suggesting that some of the psychomotor tests may not be sensitive enough to identify the differences between different second-generation antihistamines, whereas most tests were sensitive enough to identify the differences between first and second generations. Previous studies have clearly shown that psychomotor measurements displayed adequate sensitivity for comparisons of placebo and the first-generation antihistamines35 and of the first and second generations.44
The present findings support previous studies in which fexofenadine, at recommended doses (60-120 mg) and even at extremely high doses (240-360 mg), did not cause any psychomotor impairment in human volunteers.9,24-26 In contrast, previous studies have shown that loratadine resulted in cognitive impairment at higher than recommended doses (20-40 mg),1,10 whereas at recommended doses of 5 to 10 mg, cetirizine has been evaluated as being either nonsedating11,13,14,17,18,21,23 or mildly sedating.16,20,22 The results with cetirizine are variable, and at higher than recommended doses (20 mg), the agent has been reported to produce significant drowsiness12 and impairment in a selected task14 in some studies but no cognitive impairment in others.11,12
In addition, in a recent meta-analysis performed to obtain an index of the sedative profiles of antihistamines,29,30 the proportional impairment ratios (PIRs) from objective (O) tests for fexofenadine, cetirizine, and hydroxyzine were 0.00, 0.18, and 2.25, respectively, and 0.00, 0.33, and 2.57, respectively, from subjective (S) tests.30 In addition, fexofenadine showed the lowest index for both PIR-O and PIR-S among all 23 antihistamines on the database.30 The PIR values are based on various performance tests, including actual car driving or driving simulator tests; psychomotor tests such as CRT, critical flicker fusion (CFF), and tracing tasks; and learning and memory tests.8,9,11,13,14,16-19,21-26,35,44 A smaller PIR value corresponds to a weaker sedative effect.
The results of the current PET analysis showed that cetirizine occupied H1Rs in the cerebral cortex (mean value for cortex: 26.0%, ranging from 17.3%-40.5% according to the location), whereas fexofenadine demonstrated negligible cerebral H1R binding (mean value for cortex: -0.1%, ranging from -14.8%-5.6%, varying according to the location in the cortex). The amount of binding in the cingulate cortex was below zero (-14.8%), which is probably due to the control BP values being obtained from different subjects and the resulting interindividual differences. In general, fexofenadine appears to have the least ability of all the antihistamines tested so far to cross the BBB,33 and the present study indicates that PET could be a very sensitive measurement of the H1R blockade, which could be an alternative index of impairment due to antihistamines.
Previous PET studies have indicated that the orally administered first-generation antihistamines, such as d-chlorpheniramine 2 mg,33,35 ketotifen 1 mg,33 and diphenhydramine 50 mg,36 had H1RO values of about 77%, 77%, and 60%, respectively, whereas the second-generation antihistamines, terfenadine and ebastine, occupied about 12% to 17%32,33 and 10%,34 respectively, of the available H1Rs in the brain. In addition, a previous PET study comparing antihistamine H1RO in the cortical brain areas showed a high degree of binding with diphenhydramine 50 mg, blockade in the frontal cortex with cetirizine 20 mg, but no binding with fexofenadine 180 and 360 mg.36 These findings further support the current study and suggest that PET is applicable in the evaluation of the sedative properties of antihistamines.
The Consensus Group on New Generation Antihistamines (CONGA) was convened in 2002 under the auspices of the British Society for Allergy and Clinical Immunology (BSACI). The recent proposal from CONGA accurately summarizes the situation concerning the evaluation of the sedative profiles of antihistamines,42 stating that all of the following 3 measurements should be undertaken to classify a specific antihistamine as nonsedating: (1) incidence of subjective sleepiness, (2) objective cognitive and psychomotor functions, and (3) PET measurement of H1RO. All of these aspects were examined in the present study.
For evaluation of the incidence of subjective sleepiness, double-blind, placebo-controlled studies should be performed in a relatively large population sample, and no statistically significant difference should be observed between placebo and the target drug. Similarly, cognitive studies should be conducted in a large population sample, and no significant differences should be observed between placebo and the active treatment in at least 2 different tasks. The dose of the positive internal control should be carefully chosen to establish the sensitivity of the cognitive tests, and the dose for a new target agent should be the highest recommended dose. The target agent should also be examined for H1RO to confirm its nonsedative profiles. The recommended criterion for H1RO is a maximum of around 20% at the highest recommended dose.42 Following these recommendations, when any impairment of central nervous system (CNS) function is demonstrated for the target agent, it should be classified as a "relatively nonsedative" or "less sedative" drug, not a "nonsedative" drug. A lack of CNS effect should be recognized as an important prerequisite for new-generation antihistamines, and nonsedative properties should be certified only when the above-mentioned criteria have been fulfilled.42
In this point, it seems that fexofenadine 120 mg can fulfill the prerequisite for a nonsedating antihistamine because all measures for subjective sleepiness and cognitive impairment showed no difference compared with placebo and always showed a significant difference to the active control. The H1RO for fexofenadine also showed no difference to the baseline value. With very high probability, it can be estimated that fexofenadine 60 mg will give the same result. In contrast, it seems that cetirizine 20 mg can not fulfill the prerequisite for a nonsedating antihistamine because some measures for subjective sleepiness and cognitive impairment showed significant differences to placebo, and it did not show a significant difference compared with the active control. The H1RO for cetirizine 20 mg was also higher than baseline.
According to the CONGA recommendations, all of the comparisons should be examined at the highest recommended dose in each country to confirm nonsedating profiles of specific antihistamines. In Japan, the recommended single dose is 60 mg for fexofenadine and 10 mg for cetirizine; the recommended maximum daily dose at the time of the study was 120 mg for fexofenadine and 20 mg for cetirizine. However, it is not specified in the CONGA recommendations if the highest recommended dose should be taken "per dose" or "per day" in an oral administration. In contrast, because the clinical use of antihistamines at higher than the manufacturers' recommended doses is widespread, it is important and essential that all drugs are tested at supraclinical dose ranges. Therefore, we employed 120 mg fexofenadine and 20 mg cetirizine in this study. This "double-dosing" design was demonstrated to be useful to highlight the potentially small difference between different second-generation antihistamines. The issue of overdosing and multiple dosing would make it important to separate one drug category, which has little impairment at low or recommended doses but causes dose-related impairment at higher doses, from another category, which does not cross the BBB, inducing no sedative side effects even at higher doses.
In summary, the findings in this study show that PET was the most sensitive technique for differential comparison of second-generation antihistamines. Fexofenadine 120 mg was clearly distinguishable from cetirizine 20 mg in terms of psychomotor retardation and H1RO, with the latter showing that fexofenadine does not penetrate the BBB. These results suggest that fexofenadine can be functionally separated from the second-generation antihistamines to establish a new category of "third-generation" or "truly nonsedating" antihistamines in terms of drugs that do not cross the BBB even at high doses. However, these results should be taken cautiously, as it is not yet clear whether the comparison of H1RO with recommended single doses of fexofenadine (60 mg) and cetirizine (10 mg) would provide the same results. Further PET measurements would be needed for this purpose.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication July 21, 2003; Revised version accepted May 22, 2004.
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REFERENCES |
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