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`CCTM NeloLaem Epes
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`Drugs of today. (iM)
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`DRUGS OF TODAY
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`Drugs of Today 2004, 40 (5): 415-421
`Copyright © 2004 PROUS SCIENCE
`CCC: 0025-7656/2004
`
`LEVOCETIRIZINE
`A newselective H, receptor antagonist for use in allergic disorders
`James H. Day'?, Anne K. Ellis’? and Elizabeth Rafeiro'
`'Division of Allergy and Immunology, Kingston General Hospital:
`2Department of Medicine, Queen’s University, Kingston, Ontario, Canada
`
`CONTENTS
`415
`Summary ...-. 0.02000 e eee
`Dee eee eee ene 415
`Introduction. ........ 0.2.0.
`Cee ee eee tenes 416
`Pharmacology .......-.0.+++e55
`rr 416
`Pharmacodynamics ........-+--
`Dee eee rete eee 417
`Pharmacokinetics..............
`417
`Therapeutic efficacy ..........00.
`418
`ee
`Safety and side-effect profile.......
`See ete eee etn 419
`Commentary. ....-. 0.00000 ee eee
`419
`References... 0... ce ees
`
`Summary
`Levocetirizine is the active R-enantiomer of ce-
`tirizine and represents a new second-generation
`histamine H, antagonist. It has a high affinity and
`selectivity for H, receptors. Comparative studies
`have shown evidenceof superior H, receptor bind-
`ing affinity over its racemate, cetirizine. Levocetiri-
`zine has a favorable pharmacokinetic profile;
`it is
`rapidly and extensively absorbed, minimally meta-
`bolized, and has a lower volume ofdistribution (V4)
`than someother second-generation antihistamines.
`A number of studies using the histamine-induced
`wheal and flare model have repeatedly demon-
`
`"Oe
`
`Correspondence: Dr. James H. Day,Division of Allergy
`& Immunology, Kingston General Hospital, 76 Stuart St,
`Kingston, ON, Canada K7L 2V7.Tel.: (613) 548-2336; FAX:
`(613) 546-3079; E-mail: dayj @kgh.kari.net
`
`strated marked suppressive effects for levocetiri-
`zine. Levocetirizine has also been found to be effec-
`tive in relieving symptoms of seasonal and peren-
`nial allergic rhinitis, including nasal congestion,
`and its side effects are minor. © 2004 Prous Science.All
`rights reserved.
`
`Introduction
`Levocetirizine is a newly developed selective
`H, antagonist.It is the A-enantiomeror active isomer
`(eutomenof the racematecetirizine, a second-gen-
`eration antihistamine. The less active S-enantiomer,
`or distomer, is dextrocetirizine (Fig. 1). There is no
`evidenceofchiral inversion (i.e., racemization) ofle-
`vocetirizine in the body, a finding which is indicative
`of its stability (1, 2).
`Available in several countries in Europe and in
`Asia,
`levocetirizine is marketed mainly under the
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`416
`
`
`
`
`(S)-dextrocetirizine
`
`(R)-levocetirizine
`
`wok,
`O
`
`Fig. 1. Chemicalstructures of (A}-levocetirizine and (5)-
`dextrocetirizine.
`
`trade names Xyzal® and Xusal® for the treatment
`of seasonal allergic rhinitis, perennial allergic rhini-
`tis and chronic idiopathic urticaria. This review will
`examine the pharmacology, therapeutic efficacy
`and safety of levocetirizine.
`
`Pharmacology
`Pharmacodynamics
`Receptor binding
`Levocetirizine is a competitive antagonist of
`histamine H, receptors (3) andis at least 600 times
`more selective for H, histamine receptors than for
`a variety of other G-protein-coupled receptors (4).
`Binding studies using cloned human H, receptors ex-
`pressed in Chinese hamster ovary cells have shown
`that levocetirizine has a twofold higher affinity for
`H, receptors than cetirizine and an approximately
`30-fold higher affinity than its enantiomer dextroce-
`tirizine (5, 6). The carboxyl group of levocetirizine
`interacts strongly with the Lys!’ residue of the hu-
`man H, receptor, and this interaction is considered
`keyto its long half-time of dissociation (6).
`
`Histamine wheal and flare
`and nasal histamine challenge studies
`A number of studies have confirmed levocetiri-
`zine to be the active enantiomer of cetirizine, and
`dextrocetirizine the inactive enantiomer. One study
`
`Levocetirizine
`
`compared levocetirizine (2.5 mg) with cetirizine
`(5.0 mg) and dextrocetirizine (2.5 mg) using the
`histamine-induced nasal response model (7). Both
`jevocetirizine and cetirizine significantly reduced
`sneezing and inhibited the histamine-induced in-
`crease in nasal airway resistance by nearly 50%,
`which was not observed with dextrocetirizine or
`placebo. In a study by Devalia ef a/. (8), the effects
`of these compounds were compared using the his-
`tamine-induced wheal and flare model in the skin. In
`this randomized, double-blind, crossover study us-
`ing healthy volunteers, both cetirizine and levocet-
`iriziné produced a marked inhibition of histamine-
`induced wheal and flare, an effect not observed with
`dextrocetirizine. Inhibition by levocetirizine of both
`the wheal and flare responses was apparentin one
`hour, with inhibition of the wheal response lasting
`for a mean duration of 28.4 hours and with a max-
`imal inhibition of 83.8% at 6 hours post-treatment.
`Inhibition of the flare response lasted a mean dura-
`tion of 26.0 hours, with a maximal inhibition of 83.6%
`at 6 hours. While cetirizine produced similar inhibito-
`ry effects on these parameters, levocetirizine pro-
`duced a greater effect than cetirizine on histamine-
`induced wheal from 0-32 hours postdose as cal-
`culated from the area under the curve (AUC, mean
`wheal area vs. time),
`The effects of levocetirizine 5 mg were com-
`pared to those of loratadine 10 mg and placeboin
`terms of the wheal and flare response to intrader-
`mal histamine injection as well as subjects’ self-rat-
`ing of skin itch at 4 hours postdose (9). Levocetiri-
`zine significantly reduced flare, wheal and itch by
`60%, 68%and 91%, respectively, while the effects
`of loratadine were variable and not significantly dif-
`ferent from those of placebo. Another histamine-in-
`duced wheal and flare study compared levoceti-
`rizine 5 mg, ebastine 10 mg, fexofenadine 180 mg,
`loratadine 10 mg, mizolastine 10 mg and placebo
`in single doses (10). The overall effect of each drug
`was evaluated by the AUC for inhibition of wheal
`and flare over 24 hours. In this study, levocetirizine
`produced the greatest suppression of wheal and
`flare surface areas, followed by ebastine, fexofe-
`nadine and mizolastine—all of which had compara-
`ble effects. Loratadine produced the least suppres-
`sion. A similar double-blind, randomized, crossover
`study involved 12 healthy volunteers who received
`a single dose of levocetirizine 5 mg, desloratadine
`5 mg or placebo. When the AUC versus time for
`the wheal and flare response over 24 hours were
`compared, levocetirizine suppressed skin reactivity
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`J.H. Day, A.K. Ellis and E. Rafeiro
`
`417
`
`to histamine to a greater degree, more consistently
`and for a longer duration than desloratadine (11).
`Another comparison of these same treatments in 18
`healthy volunteers showed that levocetirizine and
`desloratadine were superior to placebo, and levo-
`cetirizine was superior to desloratadine.
`‘Total’
`wheal inhibition (95%) occurred only with levace-
`tirizine, and the median duration of 70%whealin-
`hibition with this compound was 21.4 hours (12).
`
`Antiallergic activity
`Twoin vitro studies have shown evidence of ant-
`inflammatory activity for levocetirizine. Michel et ai.
`(13), using the skin chamber technique, found pre-
`liminary evidence that levocetirizine at therapeutic
`doses produces three main antiinflammatory effects:
`a decreasein eosinophil recruitment and a reduction
`in both soluble VCAM-1 release and protein levels
`affecting vascular permeability. Levocetirizine has
`also been found to inhibit eotaxin-induced eosino-
`phil transendothelial migration (14).
`
`Pharmacokinetics
`
`Absorption
`Levocetirizine undergoes rapid absorption, as
`evidenced by a maximal plasma concentration
`(0.27 + 0.04 pg/ml) at 0.75 hours (t,,,,) following
`administration of a single oral dose of 5 mg of the
`'4C-radiolabelled compound. its extensive absorp-
`tion is indicated by the recovery of 98.3%of the to-
`tal radioactivity in the urine and feces at 168 hours
`(7 days) (2).
`
`Distribution
`
`Volume of distribution (V.} is a proportionality
`factor relating the drug concentration in the blood
`or plasmato the total amountof drug in the body.It
`has been determined that the higher the degree of
`drug distribution and binding to tissue, the lower the
`concentration in the plasma, and thus the greater
`the V,. Levocetirizine has been shawn to have a
`low apparent V, which has been estimated at 0.3-
`0.41 Vkg (1,2) and is believed to be attributable to
`its relatively high plasma protein binding (91.2%)
`(15, 16). Levocetirizine’s V, is lower than several
`other second-generation antihistamines, particular-
`ly loratadine and ebastine, both of which have a V,
`estimated at >100 I’kg (17}. A low V, is desirable
`for medications in terms of bath safety and efficacy
`sinceit indicates reduced exposure of organs which
`are not therapeutic targets to the circulating drug,
`
`thereby minimizing toxicity, the potential for drug~
`drug interactions and individual variations in thera-
`peutic effect (16).
`Levocetirizine’s confinement to plasma is evi-
`denced by a whole blood to plasma ratio of 0.51—
`0.68 during the first 12 hours following a singla
`dose of [C]-levocetirizine, a finding indicative of
`minimal association with blood cells (2).
`
`Metabolism and elimination
`
`Levocetirizine is minimally metabolized; 85.8%
`of a single oral dose is excreted unchanged at 48
`hours postdosing, with only 2.4% of the total dose
`comprised of metabolites (2). Notably, levoceti-
`rizine is not metabolized by CYP 2D6, a specific
`P450 isozymethat is commonly involved in drug-
`drug interactions (1). CYP 3A4, another P450 iso-
`zyme, metabolizes antihistamines such as terfana-
`dine and astemizole. Co-administration of these anti-
`histamines with potent inhibitors of CYP 3A4 (e.g.,
`ketoconazole, erythromycin) can lead to drug ac-
`cumulation and adverse events (18). CYP 3A4is
`unlikely to play a significant role in levocetirizine’s
`restricted metabolism, but this has not been direct-
`ly evaluated.
`The half-life (t,,.) of levocetirizine has been es-
`timated at 7.05-7.8 hours (1, 2). Levocetirizine is
`largely eliminated by renal excretion, single oral
`administration of 5 mg ['“C]-levocetirizine to 4
`healthy volunteers resulted in 85.4% of the total
`dose being recovered in the urine, while 12.9%
`was recovered in feces at 168 hours (7 days} post-
`dose (2). Renal excretion of levocetirizine occurs
`by glomerularfiltration and active tubular secretion,
`and renal clearance has been estimated at 29.2
`mifmin (or 350 ml/min when corrected for protein
`binding). The nonrenal clearanceof !evocetirizine
`is relatively low(L.@., 9.70 ml/min), which reducesits
`potential for metabolism-based drug interactions (1}.
`
`Therapeutic efficacy
`Levocetirizine has been investigated far its etfi-
`cacy in seasonalallergic rhinitis. Leynadier et al.
`(19) compared 2.5, 5 and 10 mg of levocetirizine
`and placebo administered once daily far 2 weeks
`during either grass or weed pollen season in France
`and Germany.In this study, 470 patients self-rated
`their symptoms of sneezing, rhinorrhea, nasal con-
`gestion, nasal pruritus and ocularpruritus on a scale
`from 0-3 each evening by means of diary evalua-
`tion cards. Thetotal four-symptam score (T45S} was
`calculated by adding each of the individual scores,
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`418
`
`Levocetirizine
`
`excluding nasal congestion. All three doses of lev-
`ocetirizine were superior to placebo in reducing the
`mean T4SS as well as individual symptoms,with
`the exception of nasal congestion. There was 4
`simple linear relationship between levocetirizine
`dase and reduction of T4SS.
`In a randomized, double-blind, placebo-control-
`led, crossoverstudy, 39 subjects with perennialrhini-
`tis and allergy to house dust mite were challenged
`with dust mite antigen in the Vienna Challenge Cham-
`ber, an indoorallergen challenge system (20), and
`response to a single dose of levocetirizine 5 mg,
`loratadine 10 mg or placebo was recorded (21).
`A significant improvement in symptom score wasre-
`ported by 83.8% of subjects receiving levocetiri-
`zine, while only 66.7%of subjects responded to lo-
`ratadine.
`Another randomized, double-blind, placebo-con-
`trolled evaluation of levocetirizine was undertaken
`with 294 dust mite-sensitive perennial allergic rhini-
`tis subjects at multiple centers in South Africa (22).
`Subjects received either levocetirizine 5 mg or
`placebo once daily for 6 weeks. Levocetirizine pro-
`duced an 86% improvement in T48S over the first
`week of treatment and a 47% improvement over
`the entire treatment period campared to placebo.
`Levocetirizine also produced an 83% improvement
`in nasal congestion at the completion of 6 weeksof
`treatment.
`A study using the Environmental Exposure Unit
`(EEU}, an indoor pollen challenge system (23),
`compared the efficacy including the onset and du-
`ration of action of levocetirizine to that af deslo-
`ratadine (24).
`In this double-blind, placebo-con-
`trolled, parallel-group study, 373 ragweed-sensitive
`subjects were randomized to once-daily levocetiri-
`zine 5 mg, desloratadine 5 mg or placebo, and ex-
`posed to ragweed pollen on 2 consecutive days.
`Symptomswere self-rated every 30 minutes. On both
`days, levocetirizine produced a greater improvement
`in the major symptom complex score than deslo-
`ratadine; both were better than placebo. The onset
`of action of levocetirizine was 1 hour, compared to
`3 hours with desloratadine,
`Antihistamines have nottraditionally been con-
`sidered efficacious in controlling nasal congestion
`(25, 26). Beginning in 2001, a number of studies
`specifically addressed the decongestant effects of
`desloratadine and have shownit to be effective for
`this symptom (27-32). Fexofenadine (30, 33-35),
`azelastine (36, 37), ebastine (38) and cetirizine
`(39, 40) have also been shown to have deconges-
`
`tant effects. Recent studies of levocetirizine demon-
`strate that it too appears to possessthis property.
`Potter’s evaluation (22) of levocetirizine showed
`thatit provided signiftcantrelief of nasal congestion
`over 6 weeks of daily administration. A later study
`in the Environmental Exposure Unit showed that
`levocetirizine was not anly superior to placebo in
`controlling nasal congestion on both treatment days
`but also better than desloratadine on the first treat-
`ment day (24). These findings suggest that further
`characterization of levocetirizine’s decongestant
`properties is warranted.
`Levocetirizine has demonstrated beneficial ef-
`fects in chronic idiopathic urticaria and atopic der-
`matitis. In a large uncontrolled study, oral levoceti-
`rizine 5 mg once daily for 32 days was reported ef-
`fective in the treatment of both of these disorders
`in at least 80%of subjects at the end of the treat-
`ment period. Global assessments by subjects indi-
`cated efficacy ratings of either good or very goadin
`over 80%of the subject population (41).
`
`Safety and side-effect profile
`Because of acknowledged sedative effects of
`first-generation antihistamines and to some extent
`with cetirizine (42-44), there have been several eval-
`uations of levocetirizine's effect on cognition and
`psychomotor performance. Verster et al. (45) com-
`pared the effects of levocetirizine 5 mg, diphenhy-
`dramine 50 mg and placebo administered once
`daily to 48 healthy volunteers. Memory and psycho-
`motor performance were assessed acutely (day 1)
`and subchronically (day 4). Levocetirizine did not
`alter memory, divided attention or tracking perfor-
`mancetests, but diphenhydramine significantly af-
`fected performanceon tracking and divided atten-
`tion. The same study group found that diphenhy-
`dramine produced Clinically relevant impairment of
`driving performance not evident with levocetirizine
`or placebo (46).
`The impact of levocetirizine & mg, diphenhy-
`dramine 50 mg and placebo on a different battery
`of psychometric tests (47) was studied with the
`treatments administered once daily for 5 consecu-
`tive days in a three-way crossover design. Levoce-
`tirizine did not modify cognitive and psychomotor
`function tests when compared with placebo, where-
`as diphenhydramine did. Decreased alertness was
`reported by subjects in the diphenhydramine group
`but not by those taking levocetirizine.
`The sédative/psychomotor effects of levoceti-
`riziné were also investigated by Hindmarch et al.
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`J.H. Day, A.K. Etlis and E. Rafeiro
`
`419
`
`(48), In this double-blind, randomized, crossover stu-
`dy, 20 healthy volunteers received levocetirizine 5
`mg, cetirizine 10 mg, loratadine 10 mg, prometha-
`zine 30 mg or placebo once daily for 4 days. Psy-
`chometric evaluation and histamine-induced skin
`prick testing were performed at baseline and at 1,
`2,3, 4, 6, 8, 10 and 12 hours postdosing on days 1
`and 4. Promethazine (a sedating phenothiazine
`antiemetic) served as a positive control and veri-
`fied the sensitivity of the test battery. Both acute
`(single-dose) and subchronic (4-day) promethazine
`produced a deleterious impact on all psychometric
`tests. The effects of levocetirizine, cetirizine and lo-
`ratadine wereindistinguishable from those of place-
`bo for all objective and subjective tests at all time
`points on both test days. Bothcetirizine and levoce-
`tirizine produced potentinhibition of histamine wheal
`and flare compared to placebo, whereas promet-
`hazine and loratadine had lesser inhibitory effects.
`The lack of significant adverse effects of tevo-
`cetirizine treatment are suggested in the study by
`Potter (22) that involved a 6-week administration of
`a 5 mg doseoncedaily, the longest reported treat-
`ment period using levocetirizine. Subjects taking
`levocetirizine or placebo had a similar incidence of
`adverse events, with 60.0% and 68.1%reporting at
`least one adverse event, respectively. The most fre-
`quently reported adverse events for both levoceti-
`rizine and placebo groups, respectively, were head-
`ache (34.7% and 34.7%), influenza-like symptoms
`(16.7% and 13.9%) and upper respiratory tract in-
`fections (6.7% and 9.0%). The most common ad-
`verse events judgedto be related to treatment were
`headache and somnolence. The incidence of som-
`nolence was 6.0%for levocetirizine and 2.8%for
`placebo. One subject experienced an increase in
`alanine aminotransferase (ALT) that was consid-
`ered to be drug-related; it resolved spontaneously
`after 9 days. No casesofincreases in QTc intervals
`on electrocardiograms were reported.
`Although sedation has been reported for levo-
`cetirizine, significant impairment of memory or psy-
`chomotor performance has not been demonstirat-
`ed. These findings, along with the minimal side-ef-
`fect profile, indicate levocetirizine to be safe for
`patients on a daily dosing program. Dose adjust-
`ment is recommended for patients with renal or
`hepatic impairment (49).
`
`Commentary
`Levocetirizine is a recently developed second
`generation H, antihistamineavailable for the treat-
`
`mentofallergic rhinitis and urticaria. It has demon-
`strated clinical efficacy for the relief of allergic rhini-
`tis symptoms including improvement of nasal con-
`gestion. It has been suggested that levocetirizine is
`a “me too” drug—thatit is simply the active enan-
`tiomer of cetirizine offering no new benefits over the
`parent compound (50). However, based on phar-
`macokinetic and pharmacodynamic properties, a
`rationale has been offered for the chiral switch from
`the racemate to levocetirizine (16). These proper-
`ties include chiral stability, a higher affinity for H,
`receptors and a lower V, compared to cetirizine.
`There is insufficient evidence to draw conclusions
`on the clinical relevance of these findings, but in-
`formation available to date is reason for further in-
`vestigation.
`
`References
`1, Baltes, E., Coupez, R., Giezek, H., Voss, G.,
`Meyerhoff, C., Strolin, B.M. Absorption and dis-
`position of fevocetirizine, the eutomer of cetiri-
`zine, administered alone or as cetirizine to
`healthy volunteers. Fundam Clin Pharmacol
`2001, 15: 269-77.
`2. Benedetti, M.S., Plisnier, M., Kaise, J. et al.
`Absorption, distribution, metabolism and excre-
`tion of [4C}levocetirizine, the R enantiomer of
`cetirizine, in healthy volunteers. Eur J Clin Phar-
`macol 2001, 57: 571-82.
`3.Christophe, B., Carlier, B., Gillard, M., Chate-
`lain, P., Peck, M., Massingham, R. Histamine
`H, receptor antagonism by cetirizine in isolated
`guinea pig tissues: Influence of receptor re-
`serve and dissociation kinetics. Eur J Pharma-
`col 2003, 470: 87-94,
`4. Gillard, M., van der Perren, C., Moguilevsky, N.,
`Massingham, R., Chatelain, P. Binding charac-
`teristics of cetirizine and levocetirizine to hu-
`man H(1) histamine receptors: Contribution of
`Lys(191) and Thr(194). Mol Pharmacol 2002,
`61: 391-9.
`5. Gillard, M., van der Perren, C., Massingham, R.,
`Chatelain, P. Binding characteristics of PH]lev-
`ocetirizine to cloned human H1-histamine-re-
`ceptors expressed in CHO cells. Inflamm Res
`2002, 51 (Suppl. 1): S$77-S78.
`6. Gillard, M., van der Perren, C., Moguilevsky, N.,
`Massingham, R., Chatelain, P. Major role for
`the carboxylic function of cetirizine and levoce-
`tirizine in their binding characteristics to human
`H1-histamine-receptors, Inflamm Res 2002, 51
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`
`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2028 Page 7
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2028 Page 7
`
`

`

`420
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`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2028 Page 8
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2028 Page 8
`
`

`

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`UCB Biopharma SPRL(IPR2019-00400)
`Exhibit 2028 Page 9
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2028 Page 9
`
`