Lack of effect of single and repeated doses of levocetirizine, a new
`antihistamine drug, on cognitive and psychomotor functions in
`healthy volunteers
`
`J. M. Gandon1 & H. Allain2
`1Biotrial clinical pharmacology unit, rue Jean-Louis Bertrand, Technopole Atalante Villejean, 35000 Rennes and 2Faculte´ de Me´decine, 2 avenue du
`Professeur Le´on Bernard 35043 Rennes Cedex, France
`
`the active enantiomer of cetirizine, an
`is
`Aims Levocetirizine (R-cetirizine),
`antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic
`urticaria. The purpose of this trial was to analyse the effects of levocetirizine single
`and multiple doses on CNS using integrated measures of cognitive and psychometric
`performance.
`Methods A battery of psychometric tests was used: critical flicker fusion (CFF), choice
`reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective
`assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers
`received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or
`placebo once daily for 5 consecutive days (3-way cross-over). Diphenhydramine was
`used as a positive control. CFF tests were performed on days 1 and 5 at baseline and
`up to 24 h following drug intake. Subjects used the Bond-Lader visual analogue scales
`(VAS) to assess their mood and vigilance.
`Results In contrast to diphenhydramine, when compared with placebo, levocetirizine
`did not modify the CFF (primary endpoint), regardless of
`the dosing scheme
`(x1.62 Hz [x2.61, x0.64] and x0.81 Hz [x1.80, 0.19], respectively, 3 h after
`dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h
`after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar
`with levocetirizine and placebo but increased with diphenhydramine. LMT was
`similar in all three groups. No relevant difference between placebo and levocetirizine
`was recorded by the subjects on their assessment of alertness using the VAS, whilst
`decreased alertness was reported following diphenhydramine 50 mg.
`Conclusions This study showed that levocetirizine does not produce any deleterious
`effect on cognitive and psychometric functions compared with placebo in healthy
`male volunteers.
`
`Keywords: antihistamine, critical flicker fusion, levocetirizine, psychomotor perfor-
`mance, reaction time
`
`Introduction
`
`Recently developed antihistamine drugs have an increased
`benefit-risk ratio compared with first generation anti-
`histamines. As a matter of
`fact,
`the efficacy of new
`antihistamines is not correlated with sedation, which has
`been demonstrated to be minimal [1]. However, it remains
`
`Correspondence: Dr Jean-Marc Gandon, Biotrial clinical pharmacology unit, rue
`Jean-Louis Bertrand, Technopole Atalante Villejean, F-35000 Rennes, France.
`E-mail: jean-marc.gardon@Biotrial.com
`
`Received 5 September 2001, accepted 14 February 2002.
`
`that the effect of a given drug on the CNS has to be
`explored specifically, especially when this drug could be
`administered to people involved in potentially dangerous
`activities. Methodological aspects are central
`to this
`exploration, and some study designs were sometimes
`controversial in appreciating CNS effects of a given drug
`[2, 3]. Therefore, a battery of psychometric tests is essential
`to characterize the level of CNS impact of a new drug.
`Cetirizine is a chiral molecule with potent antiallergic
`effects and clinically insignificant sedative effects with
`minimal impact on routine daily activities [2–5].
`Levocetirizine (R-cetirizine) is the active enantiomer of
`cetirizine. This molecule has been shown to have both
`
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`J. M. Gandon & H. Allain
`
`important affinity and selectivity for H1-receptors [6].
`Its affinity is 2 times and 25 times higher compared with
`cetirizine and dextrocetirizine (S-cetirizine), respectively.
`Levocetirizine 5 mg has at
`least equivalent
`inhibitory
`effects on cutaneous wheal and flare responses as cetirizine
`10 mg. Conversely, dextrocetirizine does not differ from
`placebo [7]. Like cetirizine, levocetirizine is indicated for
`the treatment of allergic rhinitis (seasonal and perennial)
`and chronic idiopathic urticaria.
`The purpose of this trial was to study the effect of
`single and repeated doses of levocetirizine on integrated
`measures of cognitive and psychometric performances
`in healthy volunteers. Both a negative (placebo) and a
`positive control (diphenhydramine) were used, in order to
`assess both the sensitivity of the tests used and the effects
`of levocetirizine.
`
`Methods
`
`Drugs profile
`
`Levocetirizine is rapidly absorbed and has a fast onset of
`action, peak plasma concentrations are reached about 1 h
`after dosing and plasma half-life in adults is between 8 and
`10 h [6]. More than 85% of levocetirizine is excreted
`unchanged in the urine; the remaining fraction being
`excreted in the faeces.
`When compared with cetirizine 10 mg, levocetirizine
`5 mg demonstrates similar absorption properties, a smaller
`volume of distribution (0.4 l compared with 0.6 l), a
`lower total body clearance, and a higher fraction of
`unchanged compound in the urine. Clinical studies have
`shown that
`levocetirizine 5 mg has
`similar effects
`to
`cetirizine 10 mg on inhibition of histamine induced
`cutaneous wheal and flare and histamine induced increased
`nasal resistance and pressure [7, 8].
`Diphenhydramine is a first generation antihistamine
`with central sedative properties and anticholinergic effects.
`It is extensively metabolized; tmax and elimination half-life
`are 1.7 h and 9.2 h, respectively [9].
`The most frequently reported side-effects of diphen-
`hydramine are related to CNS depressing properties of the
`drug (sedation, drowsiness, lassitude and motor incoordi-
`nation), making it a good candidate for a positive verum.
`The dose used, 50 mg, is considered to be the lowest
`producing a change in performance test scores [10].
`
`Subjects and study design
`
`As required by the protocol, no volunteers were found to
`consume alcohol abusively, nor did they smoke more than
`10 cigarettes a day. They did not consume more than six
`cups of xanthine-containing beverages a day and none
`had any history of illicit drugs of abuse. No medication
`
`was allowed 2 weeks prior to recruitment, nor during
`the study, except for the study drugs.
`separated by a
`Three treatment periods of 5 days
`wash-out period of at least 7 days were planned (Figure 1).
`The last visit was a follow-up visit that occurred within
`the week following the last study drug administration.
`Subjects were hospitalized in the Study Unit during the
`5 day treatment periods. No blood samples were taken
`except for safety assessments during screening and at the
`end of the study. Meals were standardized and subjects
`had to refrain from intense physical activity, smoking,
`alcohol and grapefruit juice. Study drugs were assigned
`according to a Latin-square based randomization list.
`During each of the three treatment periods study drugs
`were administered every morning to the subjects, after
`breakfast, from day 1 to day 5. Capsules were identically
`matched in size, colour and shape,
`to respect
`the
`double-blind nature of the study.
`Every subject gave his written consent and complied
`with the French law Huriet related to biomedical research.
`The study protocol, the Subject Information Sheet and
`the Informed Consent Form were approved by the
`Independent Ethics Committee (Comite´ Consultatif
`de Protection des Personnes se preˆtant a` la Recherche
`Biome´dicale – CCPPRB) of Brest (France).
`
`Study objectives
`
`the effect of
`to assess
`The primary objective was
`levocetirizine 5 mg after both single and repeated doses,
`on psychometric and cognitive functions compared with
`placebo, using the critical flicker fusion test.
`Secondary objectives included assessment of effects on
`a battery of tests including choice reaction time, body
`sway, and on learning memory. Besides,
`subjective
`perception of mood changes and vigilance were also
`measured through visual analogue scales.
`
`Cognitive and psychometric tests
`
`Critical flicker fusion (CFF)
`The critical flicker fusion test is a widely recognized
`and validated tool
`for measuring an integrated index
`of CNS activity. The CFF threshold is an integrated
`index of CNS activity, i.e. alertness and cortical arousal
`particularly sensitive to impairment
`[4, 11, 12]. The
`frequency at which a light source must oscillate before it
`appears flicker-free is called the critical fusion frequency
`or critical flicker frequency. Subjects were asked to
`indicate when a red-light-emitting flickering source
`increasing in frequency,
`is perceived to become a
`continuous signal. They were also required to distinguish
`the threshold at which a flickering signal was perceived
`from a continuous signal, when frequency decreased.
`
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`Initial visit
`
`Period 1
`
`Washout
`
`Period 2
`
`Washout
`
`Period 3
`
`Post-
`treatment
`visit
`
`Lack of effect of levocetirizine on CNS functions
`
`Levocetirizine,
`Diphenhydramine
`or Placebo
`
`Levocetirizine,
`Diphenhydramine
`or Placebo
`
`Levocetirizine,
`Diphenhydramine
`or Placebo
`
`Day –14 to Day –1
`
`D0–D6
`
`At least
`7 days
`
`D0–D6
`
`At least
`7 days
`
`D0–D6
`
`Within
`1 week after
`final dosing
`
`Hospitalization
`
`Ambulatory
`
`Hospitalization
`
`Ambulatory
`
`Hospitalization
`
`Figure 1 Study design.
`
`This fusion and flicker are a reliable measure of cortical,
`alertness and arousal and reasonably stable in a given
`subject. Decrease in thresholds are indicative of altered
`CNS function.
`
`Choice reaction time (CRT)
`The CRT requires that the subject makes a decision and
`choose a response. CRT is based on a memory search
`paradigm [11, 13], where subjects are asked to react as
`quickly and accurately as possible in matching responses
`to a given stimuli. This procedure tests the time (in ms)
`taken by a subject to make a motor response to a sensory
`stimulus. The subject has to operate the correct button to
`switch off one of six light-emitting diodes located on a
`panel. The scores used for analysis are the mean values of
`the various times (CRT) obtained from a maximum of
`50 stimuli. An increase in CRT values would be indicative
`of impaired alertness.
`
`Body sway (BS)
`BS is a technique enabling the measurement and recording
`of involuntary anterior-posterior and left-right postural
`oscillations using a vertical force platform. Both subject’s
`positioning and equipment are standardized, in accordance
`with recommendations from the International Society
`of Posturography [14, 15]. The computerized measures
`used for analysis reflects the total displacement distance
`(cm from the centre of gravity and its corresponding
`surface (cm2)). The test is performed with both eyes open
`and closed. Body sway is increased in case of alcohol
`consumption; this is an indirect measure of alertness.
`
`Learning memory test (LMT)
`This test assesses short and long-term memory [16]. The
`subjects are asked first
`to freely recall
`the 15 words
`presented to them; then, to recall again the memorized
`words after a delay of 3 min during which he or she
`performs a digit symbol substitution test (DSST, used as a
`prolonged distraction task). The number of accurate words
`recalled determines the scores of immediate and delayed
`free memory recall.
`
`Bond and Lader’s visual analogue scale (VAS)
`These subjective assessments of mood and vigilance are
`recorded using 16 horizontal 100 mm scales. Drugs effects
`on three parameters were calculated by factorial analysis,
`namely: alertness, contentedness and calmness [17].
`CFF, CRT, BS and VAS were performed at the initial
`visit and on day 0 of period 1 to familiarize the subject
`with the procedures. They were further performed on
`day 1 and day 5 of each treatment period 1, 2, 3, 5 and
`12 h after study drug administration, then again on day 2
`and day 6, 24 h after dosing.
`LMT and DSST were performed at the initial visit and
`on day 0 of period 1 to familiarize the subject with the
`procedures. They were also performed on day 1 and day 5
`of each treatment period, before and 2 h after drug
`administration.
`
`Safety assessments
`
`A physical examination was performed by a physician at
`the initial visit, on day 6 of each study period and at each
`post-treatment visit. Cardiovascular safety was monitored
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`J. M. Gandon & H. Allain
`
`by means of standard 12-lead ECGs at the initial visit, on
`day 1 and day 5, both before and 1 h after study drug
`administration, of each period and at the post-treatment
`visit. Vital signs (blood pressure and heart rate) were
`recorded at the initial visit and on day 6 of each period
`and at the post-treatment visit. All adverse events and
`undesirable experiences occurring during the study were
`reported.
`
`Statistical analysis
`
`The primary variable was expressed as the change in CFF
`score between the baseline score (predrug administration)
`and the one obtained at
`the predefined time points
`on day 1.
`This was an exploratory study for which sample size
`was based on experience in similar
`studies
`[4, 21].
`Sufficient volunteers had to be selected by the investigator
`in order to have a total number of 18 evaluable subjects
`for the analysis. Withdrawn subjects were replaced for
`this reason.
`A repeated measures analysis of variance was used to
`compare treatment changes from baseline for this three-
`way crossover study [18, 19]. Statistical tests were carried
`1
`out two-tailed at the 5% level of significance using SAS
`software.
`included treatment effect, period
`The fixed effects
`effect,
`time-point effect and the interaction of
`treat-
`mentrtime-point effect. The baseline value was included
`into the model as a covariate. In presence of a significant
`treatmentrtime–point
`interaction,
`the treatment was
`evaluated at each time-point in the same model. The
`95% confidence intervals of
`the least-squares means
`treatment differences were calculated for pairwise com-
`parisons. Some model checks were performed: normality
`of residuals, absence of outliers (residual vs predicted
`values), and correlation between subject’s effects and their
`predicted values.
`Secondary variables were the change in CFF score
`between baseline and the predefined time points on day 5
`as well as the changes between baseline scores and those
`obtained on day 1 and day 5 for CRT, BS, LMT and
`VAS parameters. Descriptive statistics and 95% confidence
`intervals (CI) of the mean treatment differences were
`calculated.
`
`Results
`
`Disposition of subjects
`
`Thirty-one subjects were screened, 19 were included out
`of whom 18 completed the study. Out of the 19 subjects
`randomized, one withdrew his consent when under
`diphenhydramine treatment. Therefore, 19 received
`
`diphenhydramine, 18 received levocetirizine and 18
`placebo treatment. They were aged between 20 and 39
`years [mean (s.d.): 24.5 (4.2)], weighed between 56 and
`82 kg [71.0 (7.3)], and were between 166 and 189 cm in
`height [178.3 (6.0)].
`
`Critical flicker fusion test (CFF)
`
`At baseline, mean (ts.d.) CFF baseline values were
`in the levocetirizine (30.9t3.2 Hz), placebo
`similar
`(30.7t3.3 Hz)
`arm (31.0t
`and diphenhydramine
`2.7 Hz). During the first 24 h following drug adminis-
`tration, placebo and levocetirizine mean CFF values
`fluctuated around the baseline values within a range that
`never surpassed 0.5 Hz below or above baseline values,
`which corresponds to expected and acceptable fluctua-
`tions. Of note, levocetirizine and placebo results were
`never statistically significantly different from each other,
`neither globally over all time points (P=0.292), nor at
`any particular time point. By contrast, mean CFF values,
`after diphenhydramine administration displayed a maxi-
`mum decrease within 1 h of dosing, with a mean decrease
`from baseline of 1.35 Hz. The difference between
`diphenhydramine and placebo was statistically different
`globally (P=0.019) and more specifically 1, 2 and 3 h after
`dosing (P<0.04). The maximum difference between
`placebo and diphenhydramine occurred at the third hour
`with a mean difference of 1.62 Hz (P=0.002, Table 1).
`This difference was more than twice the mean difference
`observed between levocetirizine and placebo (Figure 2).
`After 4 consecutive treatment days, i.e. on day 5, CFF
`times evolution were globally similar to those of day 1
`for levocetirizine and placebo. Again, diphenhydramine
`
`Table 1 Mean treatment differences between levocetirizine
`(or diphenhydramine) and placebo in CFF from baseline on day 1
`by time-point.
`
`Comparisons
`
`Levocetirizine vs placebo
`
`Diphenhydramine vs placebo
`
`Mean difference and
`95% CI (Hz)
`
`Time
`
`P values
`
`1 h x0.15 (x1.15, 0.84)
`0.764
`2 h x0.08 (x1.07, 0.92)
`0.876
`3 h x0.81 (x1.80, 0.19)
`0.111
`5 h x0.69 (x1.69, 0.30)
`0.168
`12 h x0.27 (x1.27, 0.72)
`0.56
`24 h x0.34 (x1.34, 0.65)
`0.491
`1 h x1.04 (x2.03, x0.06) <0.05
`2 h x1.14 (x2.13, x0.16) <0.05
`3 h x1.62 (x2.61, x0.64) <0.005
`5 h x0.71 (x1.70, 0.27)
`0.152
`12 h x0.78 (x1.76, 0.21)
`0.120
`24 h x0.20 (x1.18, 0.78)
`0.685
`
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`Lack of effect of levocetirizine on CNS functions
`
`33
`
`32
`
`31
`
`30
`
`29
`
`CFF (Hz)
`
`28
`
`0
`
`1
`
`12
`Time (h)
`Figure 2 Effect of levocetirizine 5 mg (#, solid line), diphenhydramine 50 mg (%, dashed line) and placebo (%, dotted line)
`on CFF thresholds in healthy volunteers: Mean (ts.e. mean) of CFF (Hz) on day 1 – ITT population.
`
`2 3
`
`5
`
`24
`
`produced a decrease, albeit less pronounced than that
`on day 1 and no longer achieving a statistically significant
`difference relative to placebo.
`
`A similar pattern was observed with the mean difference
`in surface displacement between diphenhydramine and
`placebo: 3.08 cm2 (95% CI: 0.76, 5.39) at the 3rd hour
`after dosing on day 1.
`
`Choice reaction time (CRT)
`
`The baseline mean (ts.d.) CRT values on day 1 were
`for placebo (433.7t33.9 ms),
`similar
`levocetirizine
`(434.3t50.8 ms)
`(422.5t
`and
`diphenhydramine
`59.7 ms).
`However, a decrease in mean CRT scores was observed
`during the study, both after levocetirizine and placebo
`administration from the first to the 24th hour after dosing
`(with a maximum of x34.4 ms and x41.1 ms at the
`12th hour for placebo and levocetirizine, respectively).
`Levocetirizine was not statistically different from placebo
`at any time point. The reduction in CRT was much less
`with diphenhydramine with mean scores of x23.6 ms
`at the 12th hour. Mean CRT values on day 1 are shown in
`Figure 3. Mean CRT scores were comparable over time
`for the three treatments, with no significant differences
`for groups on day 5.
`
`Body sway
`
`from
`Results on distance and surface displacement
`the centre of gravity measured eyes open or closed,
`were similar for levocetirizine and placebo, whereas an
`increase in total displacement distance was recorded up to
`3 h after dosing with diphenhydramine on day 1. This
`increase reached statistical significance when the test was
`performed with eyes closed: at 3 h the mean difference
`between diphenhydramine and placebo was 16.35 cm
`(95% CI: 5.61, 27.10).
`
`Bond & Lader’s Visual Analog Scales (VAS)
`
`Alertness
`Scores of alertness increased both after levocetirizine and
`after placebo treatment, with a maximum at the 12th hour
`after dosing. These increases were more marked for
`placebo arm compared with levocetirizine, leading to a
`statistical difference between the two groups, at the 3rd
`and 12th hour after dosing,
`i.e. a mean VAS score
`difference of x7.87 (95% CI: x15.15, 0.60) and x8.47
`(14.05, x2.88), respectively.
`A major and significant decrease in alertness was
`observed after diphenhydramine administration, on day
`1, at the 2nd and 3rd hour after dosing, when compared
`with placebo. These mean differences (x13.51; 95% CI:
`x26.09, x0.92 and x17.09; 95% CI: x28.89, x4.28,
`respectively) were expected, diphenhydramine being a
`positive control.
`
`Contentedness
`Results pointed to a similar evolution of contentedness in
`all three treatments on days 1 and 5.
`
`Calmness
`No marked or consistent decreases in calmness were
`observed with any treatment.
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`J. M. Gandon & H. Allain
`
`20
`
`10
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`CRT (ms)
`
`–50
`
`0
`
`1
`
`2 3
`
`5
`
`24
`
`12
`Time (h)
`Figure 3 Effect of levocetirizine 5 mg (#, solid line), diphenhydramine 50 mg (%, dashed line) and placebo (%, dotted line)
`on CRT on day 1: mean time changes from baseline, in ms (ts.e. mean).
`
`Learning memory test (LMT)
`
`Immediate memory
`The results observed were not a decrease of performance,
`but rather an effect of time with a decrease from baseline
`to 2 h following the administration of all drugs including
`placebo on both day 1 and day 5. The decrease was the
`most marked with diphenhydramine on day 1, 2 h after
`administration, when compared with placebo and to
`levocetirizine on immediate first recall. However, these
`differences when compared with placebo did not reach
`statistical significance. Levocetirizine was not significantly
`different from placebo either on day 1 or on day 5.
`
`Delayed memory
`Results on delayed memory displayed the same character-
`istics as
`those on immediate memory: a decrease of
`performance for all study treatments when compared
`to baseline, greatest performance fall observed under
`diphenhydramine and finally, performance less affected on
`day 5 than on day 1.
`
`Safety assessment
`
`No serious adverse events were reported. Sixteen (16)
`subjects out of 19 exposed to study drugs experienced
`at least one adverse event (AE), of mild to moderate
`intensity. They consisted mainly in somnolence, asthenia,
`headache and diarrhoea episodes. However, both the
`incidence of AEs and the number of
`subjects who
`experienced at
`least one AE, were greater under
`diphenhydramine when compared with levocetirizine
`and placebo (occurrences/number of subjects: 20/9, 15/7,
`15/8, respectively).
`
`No apparent difference was observed between the
`three treatments with regard to the number of adverse
`events related to the study drug. The main adverse event,
`somnolence, was chiefly reported after the diphenhydra-
`mine (7 episodes reported) and placebo (6 episodes
`reported). Only 4 somnolence episodes were reported
`during
`levocetirizine
`treatment. The
`number
`of
`subjects
`suffering from somnolence was, respectively,
`2 with levocetirizine, 2 with placebo and 4 with
`diphenhydramine.
`No clinically significant changes in laboratory para-
`meters or in vital signs, or in ECG parameters were
`observed after either treatment.
`
`Discussion
`
`The purpose of this study was to assess the impact of a
`new H1-receptor antagonist, levocetirizine, on psycho-
`motor and sensorimotor performance using tests
`that
`are validated surrogate markers of CNS impairment and
`performance of daily activities.
`levocetirizine,
`Cetirizine,
`the parent compound of
`has demonstrated convincing evidence in verum and
`placebo controlled studies
`that objective measures of
`the incidence of somnolence and CNS impairment at
`therapeutic doses were similar to that produced by placebo
`[2]. As a result, the therapeutic index of cetirizine is much
`wider than the one of the first generation of H1-receptor
`antagonists.
`Levocetirizine is the eutomer of cetirizine and has
`been shown to have equivalent efficacy and tolerability at
`half the cetirizine dose. We did not expect that levo-
`cetirizine would have a deleterious effect on CNS. How-
`ever as impact on potentially dangerous daily activities
`
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`Lack of effect of levocetirizine on CNS functions
`
`(e.g. driving) remained of concern, it seemed appropriate
`to measure objectively any potential effect after single and
`repeated active doses of levocetirizine.
`The well recognized positive control used in this study
`is an antihistamine of the first generation and clearly
`induced CNS impairment in the tests performed, therefore
`validating the methodology used. Diphenhydramine
`exhibited its negative effect in the tests used, specifically
`on day 1.
`the most commonly used task in studies
`CFF is
`investigating the central effects of antihistamines and has
`proved sensitive to a wide range of compounds. CFF
`has consistently demonstrated the reduction in cognitive
`capacity following traditional antihistamines, as well as
`detecting changes
`following other antihistamines, e.g,
`loratadine and cetirizine, where other tests have failed to
`detect any impairment [11].
`CFF was used as an index of global cortical arousal [12]
`and as the primary endpoint of this study. This sensitive
`and validated test did not elicit any clinically relevant
`or statistically significant difference between levocetirizine
`and placebo. These observations, indeed, point to the
`anticipated conclusion that
`levocetirizine does not
`induce any reduction in vigilance.
`All effects were less marked on day 5, reflecting
`the development of tolerance to the treatments [13].
`
`increase in performance of CFF on
`The consistent
`day 5 is a sign of tolerance to the sedative action of
`diphenhydramine after multiple dosing (tachyphylaxis).
`As
`to the CRT test, positive results would have
`indicated impairment of psychomotor speed. The data
`in this study pointed to negative values, i.e. an increase in
`performance for both placebo and levocetirizine, even
`more so for the latter. This may be explained not by a
`learning effect as subjects were already trained in the
`method, but by a slight increase in alertness over the
`course of the study day, which is consistent with results
`obtained with the visual analogue scales. This type of
`result with significant effect of time justifies the necessity
`of using a verum and a placebo control group for
`evaluating CNS effect of antihistamines [20]. In com-
`parison, the close to null effect after diphenhydramine
`treatment would tend to signify, then,
`impairment of
`reaction speed.
`The remaining, more ancillary tests had their sensitivity
`also validated, with diphenhydramine showing a negative
`impact on performance at least on day 1. The results
`accumulated a body of evidence showing that levocetir-
`izine was never different from placebo on day 1 or on
`day 5 (Table 2).
`Overall, the smaller effects found on the 5th day in
`comparison with the first, the results of the tests also
`
`Table 2 Mean treatment differences between levocetirizine (or diphenhydramine) and placebo with 95% CI at 1, 2 or 3 h time point for
`the main trial tests, at day 1 and day 5.
`
`1 h
`
`Levocetirizine 5 mg
`2 h
`
`3 h
`
`1 h
`
`Diphenhydramine 50 mg
`2 h
`
`3 h
`
`x0.08
`(x1.07, 0.92)
`x7.33
`(x31.78, 17.11)
`2.42
`(x9.11, 13.94)
`0.61
`(x1.57, 2.80)
`x4.47
`(x12.19, 3.25)
`
`0.16
`(x0.74, 1.06)
`x8.22
`(x30.45, 14.00)
`5.73
`(x3.96, 15.42)
`x0.06
`(x1.38, 1.27)
`7.19
`(x1.12, 15.50)
`
`x0.81
`(x1.80, 0.19)
`0.22
`(x21.08, 21.53)
`6.19
`(x1.27, 13.64)
`ND
`
`x1.04
`(x2.03, x0.06)
`8.50
`(x12.76, 29.76)
`7.35
`(x0.81, 15.50)
`ND
`
`x7.87
`(x15.15, x0.60)
`
`x4.88
`(x18.04, 8.27)
`
`x1.14
`(x2.13, x0.16)
`10.00
`(x9.09, 29.09)
`7.99
`(x4.52, 20.50)
`x0.61
`(x1.93, 0.71)
`x13.51
`(x26.09, x0.92)
`
`x1.62
`(x2.61, x0.64)
`15.22
`(x2.55, 32.99)
`16.35
`(5.61, 27.10)
`ND
`
`x17.09
`(x29.89, x4.28)
`
`0.15
`(x0.56, 0.86)
`x2.11
`(x20.15, 15.93)
`6.42
`(x2.08, 14.93)
`ND
`
`0
`(x1.09, 1.09)
`6.72
`(x4.93, 18.38)
`1.63
`(x6.08, 9.33)
`ND
`
`5.47
`(x2.49, 13.43)
`
`0.31
`(x8.82, 9.44)
`
`x0.17
`(x1.27, 0.94)
`11.11
`(x6.06, 28.28)
`4.61
`(x2.35, 11.56)
`x0.56
`(x0.94, 2.05)
`x5.12
`(x13.61, 3.38)
`
`x0.63
`(x1.69, 0.43)
`12.17
`(x2.09, 26.42)
`4.97
`(x3.58, 13.32)
`ND
`
`x4.20
`(x12.55, 4.15)
`
`Test
`
`Day 1
`CFF (Hz)
`
`CRT (ms)
`
`BS Distance displ. (cm)
`Eyes closed
`LMT immediate recall
`
`VAS Alertness score
`
`Day 5
`CFF (Hz)
`
`CRT (ms)
`
`BS Distance displ. (cm)
`Eyes closed
`LMT immediate recall
`
`x0.15
`(x1.15, 0.84)
`x11.06
`(x30.32, 8.21)
`3.26
`(x1.90, 8.41)
`ND
`
`x3.78
`(x14.04, 6.48)
`
`x0.18
`(x0.91, 0.54)
`1.00
`(x14.97, 16.97)
`6.62
`(x2.20, 15.43)
`ND
`
`VAS
`Alertness score
`
`0.77
`(x4.17, 5.71)
`
`ND : Not done.
`
`f 2002 Blackwell Science Ltd Br J Clin Pharmacol, 54, 51–58
`
`57
`
`Apotex, Inc. (IPR2019-00400), Ex. 1010, p. 007
`
`

`

`J. M. Gandon & H. Allain
`
`replicate the already reported tolerance to the sedative
`properties of antihistamine drugs as tripolidine [5, 22].
`Absence of effect on memory was expected, consistent
`with the finding in an extensive review of the literature by
`Hindmarch & Shamsi [20].
`Somnolence episodes were the most frequent adverse
`event reported and were mainly observed after diphen-
`hydramine treatment, as expected. It
`is important
`to
`mention
`that
`less
`episodes were
`reported with
`levocetirizine compared with placebo.
`In conclusion, single and repeated doses of levocetir-
`izine 5 mg did not induce impairment of CNS function
`when compared with placebo in healthy volunteers. This
`is in contrast to the effects of diphenhydramine which
`served as a verum. The importance of such a positive
`control for measurement of psychomotor and cognitive
`function was demonstrated in this study.
`safe when
`It
`is concluded that
`levocetirizine is
`administered orally for 5 days in this population.
`
`The authors would like to thank Nadia Cheiab and Diane
`Kleinermans for their contribution to this study.
`
`References
`
`1
`
`Spaeth J, Klimek L, Mosges R. Sedation in allergic rhinitis is
`caused by the condition and not by antihistamine treatment.
`Allergy 1996; 51: 893–906.
`2 Hindmarch I. Psychometric aspects of antihistamines. Allergy
`1995; 50: 48–54.
`3 Rombaut NEI, Hindmarch I. Psychometric aspects of
`antihistamines: a review. Human Psychopharmacol, 1994;
`9: 157–169.
`4 Patat A, Stubbs D, Dunmore C, et al. Lack of
`interaction between two antishitamines, mizolastine
`and cetirizine, and ethanol in psychomotor and driving
`performance in healthy subjects. Eur J Clin Pharmacol 1995;
`48: 143–150.
`5 Volkerts ER, Van Willigenburg APP, Van Laar MW,
`Maes RAA. Does cetirizine belong to the new generation
`of antihistamines? An investigation into its acute and
`subchronic effects on highway driving, psychometric test
`performance and daytime sleepiness. Human Psychopharmacol
`1992; 7: 227–238.
`Investigator’s brochure UCB, Pharma RXCE, 99B0501.
`Levocetirizine dihydrochloride (UCB 28556) capsules edition
`number 2. Release date: 21st April 1999.
`7 Devalia JL, De Vos C, Hanotte F, Balte`s E. A randomized,
`double-blind, crossover comparison among cetirizine,
`
`6
`
`9
`
`11
`
`12
`
`levocetirizine, and UCB 28557 on histamine-induced
`cutaneous responses in healthy adult volunteers. Allergy 2001;
`56: 50–57.
`8 Wang DY, Hanotte F, De Vos C, Clement P. Effect of
`cetirizine, levocetirizine, and dextrocetirizine on
`histamine-induced nasal response in healthy adult volunteers.
`Allergy 2001; 56: 339–343.
`Simons KJ, Watson WT, Martin TJ, et al. Diphenhydramine.
`Pharmacokinetics and pharmacodynamics in elderly adults,
`young adults and children. J Clin Pharmacol 1990; 30: 665–671.
`10 Witek TJ, Canestrari DA, Miller RD, Yang JY, Riker DK.
`Characterization of daytime sleepiness and psychomotor
`performance following H1 receptor antagonists. Ann Allergy
`Asthma Immunol 1995; 74: 419–426.
`Sherwood N, Kerr JS. The reliability, validity and
`pharmacosensitivity of four psychomotor tests. In Human
`Psychopharmacology, Vol. 4. eds Hindmarch I, Stonier PD.
`John Wiley and. Sons Ltd, 1993; 1–14.
`Schweitzer PK, Muehlbach MJ, Walsh JK. Sleepiness
`and performance during three-day administration of
`cetirizine or diphenhydramine. J Allergy Clin Immunol 1994;
`94: 716–724.
`13 Hindmarch I. Psychomotor function and psychoactive drugs.
`Br J Clin Pharmacol 1980; 10: 189–209.
`14 McClelland GR. Body sway and the effects of psychoactive
`drugs: a review. Human Psychopharmacol 1989; 4: 3–14.
`15 Kapteyn TS, Bles W, Njiokiktjein CJ, Kodde L, Massen CH,
`Mol JMF. Standardisation in platform stabilometry being part
`of posturography. Aggressologie 1983; 24: 321–326.
`16 Allain H, Gandon JM. Psychopharmacology of memory
`components. In Human Psychopharmacology: measures and
`methods, eds Hindmarch I, Stonier PD. John Wiley and
`Sons Ltd, 1993; 4: 143–146.
`17 Bond A, Lader M. The use of analogue scales in rating
`subjective feeling. Br J Med Psychol 1974; 47: 211–218.
`18 Brown H, Prescott R. In Applied Mixed Models in
`Medicine. Chichester (England):
`John Wiley and Sons,
`1999; 408.
`Senn S. In Cross-over Trials in Clinical Research. Chichester
`(England):
`John Wiley and Sons, 1993; 266.
`20 Hindmarch I, Shamsi Z. Antihistamines. Models to assess
`sedative properties, assessment of sedation, safety and other
`side-effects. Clin Exp Allergy 1999; 29: 133–142.
`21 Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A
`double-blind, placebo-controlled investigation of the effects
`of fexofenadine, loratadine and promethazine on cognitive
`and psychomotor function. Br J Clin Pharma