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2008, Vol. 47, No. 4 (pp. 217-230)

ISSN: 0312-5963

Review Article

Pharmacology of New Antihistamines

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Clin Pharmacokinet 2008; 47 (4): 217-230REVIEW ARTICLE 0312-5963/08/0004-0217/$48.00/0

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Clinical Pharmacokinetics andPharmacodynamics of Desloratadine,Fexofenadine and LevocetirizineA Comparative Review

Philippe Devillier, Nicolas Roche and Christophe Faisy

Laboratory of Pharmacology, UPRES EA 220, Universite de Versailles Saint-Quentin, Hopital Foch, Suresnes, France

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

1. Histamine and the Histamine H1 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

2. Pharmacodynamic Properties of H1 Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

2.1 Receptor-Binding Affinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

2.2 Receptor Selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

2.3 Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

2.4 CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

3. Pharmacokinetics of H1 Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

3.1 Absorption/Metabolism/Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

3.2 Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

3.3 Duration of Action and Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

4. Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

4.1 Interactions via Active Drug Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

4.2 Interactions via Cytochrome P450 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

4.3 Possible Interactions via Renal Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

5. Use of Desloratadine and Other Second-Generation H1 Receptor Antagonists in Special Patient Subpopulations . . . . . . . . . . . . . 224

5.1 Age/Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

5.2 Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

5.3 Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

5.4 Poor Metabolizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Second-generation histamine H1 receptor antagonists were developed to provide efficacious treatment ofAbstractallergic rhinitis (AR) and chronic idiopathic urticaria (CIU) while decreasing adverse effects associated withfirst-generation agents. When comparing the efficacy and safety profiles of the newest second-generationantihistamines – desloratadine, fexofenadine and levocetirizine – many pharmacological and clinical criteriamust be considered. Most importantly, these elements should not be evaluated separately but, rather, as parts of apuzzle that create a whole picture. As a class, second-generation antihistamines are highly selective for the H1

receptor. Some bind to it with high affinity, although there is marked heterogeneity among the variouscompounds. They have a limited effect on the CNS, and clinical studies have noted almost no significant drug-drug interactions in the agents studied. No major cytochrome P450 inhibition has been reported withdesloratadine, fexofenadine and levocetirizine, and the bioavailability of desloratadine is minimally affected bydrugs interfering with transporter molecules. Of the second-generation antihistamines, desloratadine has thegreatest binding affinity for the H1 receptor. The use of desloratadine, fexofenadine and levocetirizine is not

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218 Devillier et al.

associated with clinically relevant antimuscarinic effects. Desloratadine and fexofenadine do not impaircognitive or psychomotor functioning and are comparable with placebo in terms of somnolence. Based on thesepharmacological characteristics, as well as clinical endpoints such as symptom scores, quality-of-life surveys,inflammatory cell counts and investigators’ global evaluations, we conclude that desloratadine, fexofenadine andlevocetirizine are all efficacious treatments for AR and CIU. However, differences among the antihistamines inrelation to a lack of significant interaction with drug transporter molecules and somnolence in excess of placebomay provide some advantages for the overall profile of desloratadine compared with fexofenadine andlevocetirizine.

Histamine H1 receptor antagonists are widely used in the man- 1. Histamine and the Histamine H1 Receptor

agement of a variety of allergic disorders. Second-generation H1In an allergic reaction, allergens crosslink with surface immu-receptor antagonists have largely superseded their first-generation

noglobulin E (IgE) molecules on FcεRI+ cells (e.g. mast cells andcounterparts, owing to more favourable pharmacokinetics andbasophils), causing the cells to degranulate and release histaminereduced (or negligible) sedative effects. The most frequently usedand other preformed proinflammatory mediators.[8] Four histaminesecond-generation H1 receptor antagonists are desloratadine, lo-receptor subtypes have been identified and cloned: H1,[9] H2,[10]

ratadine, fexofenadine, cetirizine and levocetirizine. These areH3[11] and H4.[12] The H2 receptor has been identified as playing adifferentiated by organic structure into the piperazine class, con-major role in gastric acid secretion.[13] Activation of the H3 recep-sisting of cetirizine and levocetirizine, and the piperidine class,tor regulates the activity of histamine and other neurotransmitterswhich includes desloratadine, loratadine and fexofenadine.in the CNS, affecting the sleep/wake cycle, cognition, caloric

Desloratadine (Clarinex1 and Aerius) is the major biologi-intake and inhibition of nociception.[14-18] Presynaptic heterolo-

cally active metabolite of loratadine. In the US, desloratadine isgous H3 receptors are also located on adrenergic, cholinergic and

approved for the treatment of seasonal allergic rhinitis (SAR) innonadrenergic-noncholinergic nerve fibres.[19-22] Activation of H3

adults and children aged ≥2 years, and perennial allergic rhinitisheterologous receptors on sympathetic nerve endings in human

(PAR) and chronic idiopathic urticaria (CIU) in adults and chil-nasal mucosa inhibit sympathetic vasoconstriction and may cause

dren aged ≥6 months.[1] In the EU, desloratadine is approved fornasal obstruction in patients with AR.[23] Histamine binding to the

the treatment of allergic rhinitis (AR), including intermittent ARH4 receptor triggers a series of signal transduction events that lead

and persistent AR, and CIU in adults and children aged ≥1 year.[2]

to chemotaxis and accumulation of eosinophils and neutrophils atFexofenadine hydrochloride (Allegra, Telfast) is the major sites of inflammation, activation of CD4+ T cells and scratching,

active metabolite of terfenadine. The US indications for fexofena- as seen in animal models. H4 receptor antagonists exerted partialdine are relief of symptoms of SAR in adults and children aged ≥2 inhibition in these models.[24-28] Current H1 receptor antagonistsyears, and relief of CIU in adults and children aged ≥6 months.[3]

have no effect on either H3 receptors or H4 receptors. In addition toIn the EU, fexofenadine is approved for relief of symptoms of their H1 receptor antagonism, new compounds with H3 and H4SAR and CIU in adults and adolescents, and relief of SAR in receptor antagonist activities may possess improved efficacy inchildren aged 6–11 years.[4,5]

allergic diseases and would represent a third generation of antihis-Levocetirizine dihydrochloride (Xyzal) is the R enantiomer of tamines.

cetirizine. Levocetirizine is approved in the US and EU for the The H1 receptor is predominantly responsible for mediatingrelief of symptoms of SAR, perennial/persistent AR and CIU in hypersensitivity reactions and allergic responses. As with the otherpatients aged ≥6 years.[6,7] histamine receptor subtypes, it belongs to the superfamily of G-

The pharmacological profiles of H1 receptor antagonists vary protein-coupled receptors with seven membrane-spanning do-from agent to agent. Although pharmacological comparisons can- mains, and is widely expressed in neurons, smooth muscle cellsnot substitute for clinical evidence, they can provide valuable and inflammatory cells.[29,30] The expression of G-protein-coupledinsight into the differences between H1 receptor antagonists. This receptors exhibits constitutive activity and exists in equilibriumreview evaluates the clinical relevance of the pharmacology of the between an active and inactive state.[31] Binding of histaminesecond-generation H1 receptor antagonists desloratadine, fex- stabilizes the receptor in the active conformation and has a proin-ofenadine and levocetirizine. flammatory effect.[32,33] As a result, mast cells and basophils

1 The use of trade names is for product identification purposes only and does not imply endorsement.

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Pharmacology of New Antihistamines 219

release increased amounts of proinflammatory mediators, includ- study of inverse agonism, desloratadine appeared to be moreing interleukin (IL)-1α, IL-β and IL-8.[34-36] Some cytokines affect potent than fexofenadine and cetirizine, a result explainable by thethe production and release of histamine as well as histamine high correlation between H1 receptor affinity and inverse agonistreceptor expression. In addition, histamine affects the balance of activity.[31,47]

both T helper (Th) cell types 1 and 2 (Th1/Th2) and immunoglobu-2.2 Receptor Selectivitylin synthesis,[37] and histamine favours the development of Th2

cells and enhances Th2-type cytokine production. However, thereSelectivity for the H1 receptor is an important characteristic ofis conflicting evidence about the effects of histamine on the Th1/

H1 receptor antagonists and ensures that adverse events mediatedTh2 balance, because the effects of histamine are dependent on theby other receptors do not occur. Desloratadine has >60 timesexpression of histamine receptors, which vary in response to Thhigher affinity for H1 receptors than it has for H2 receptors.[46]

cytokine secretion.[37,38] Upregulation of cellular adhesion mole-Similarly, neither fexofenadine nor levocetirizine binds excessive-cule expression, heightened antigen-presenting cell capacity andly to other histamine receptors at clinically relevant doses.[44,45]

increased chemotaxis of eosinophils and neutrophils are also seenThe human H1 receptor has 45% sequence homology with thein response to H1 receptor stimulation. In the CNS, H1 receptormuscarinic receptor; thus, there is the potential for interactionactivity regulates the cycle of sleeping and waking, food intake,between H1 receptor antagonists and muscarinic receptors. Thisthermal regulation, locomotion, memory and learning.[24] In theinteraction results in anticholinergic effects such as dry mouth andperiphery, H1 receptor activation contributes to the symptoms ofurinary retention, as noted with non-H1 receptor-selective first-AR and CIU (e.g. rhinorrhoea, erythema and pruritus).[8,29,39]

generation H1 receptor antagonists.[24] The affinity of deslorata-dine for muscarinic receptors is about 50- to 100-fold lower than2. Pharmacodynamic Properties of H1its affinity for H1 receptors.[45,46,48] Peak plasma concentrations ofReceptor Antagonistsdesloratadine at recommended doses for antihistaminic activity are

H1 receptor antagonists are often referred to as ‘inverse ago- 10-fold lower than the concentrations at which in vitro functionalnists’, as they bind to and stabilize the inactive form of the H1 antimuscarinic activities are observed. Desloratadine does notreceptor,[40] thereby diminishing the histamine-mediated allergic induce any clinically relevant antimuscarinic effects at therapeuticresponses associated with activation. However, because H1 recep- doses,[46,49] which is borne out by safety results from placebo-tor antagonists block both agonist-induced and constitutive ac- controlled clinical trials.[1] Fexofenadine and levocetirizine aretivity of H1 receptors, ‘double antagonist’ may perhaps be a better also devoid of any clinically relevant anticholinergic activi-term. ties.[45,50]

Blockade of human ether-a-go-go-related gene-encoded cardi-2.1 Receptor-Binding Affinity ac potassium channels can lead to a long-QT syndrome, which can

trigger torsades de pointes.[48] No interaction with cardiac potassi-Second-generation H1 receptor antagonists potently and selec- um channels has been reported with desloratadine, fexofenadine or

tively bind to the H1 receptor, stabilizing it towards the inactive levocetirizine.[6,29,51,52]

state, with relatively long dissociation times. These propertiescontribute to the effectiveness of second-generation H1 receptor 2.3 Anti-Inflammatory Effectsantagonists in alleviating histamine-mediated allergic symptomsand their long duration of action. Mediators other than histamine are involved in both the early

The binding affinities of desloratadine, fexofenadine and other and late phases of the allergic response.[8] In the early-phaseantihistamines were evaluated using a competitive binding assay response, inflammatory mediators, such as histamine, leuko-in recombinant cloned human H1 receptors expressed in Chinese trienes, bradykinin, cytokines and platelet-activating factor, arehamster ovarian cells. Binding-affinity constants were found to be released from inflammatory cells. These mediators stimulate in-0.9 nmol/L for desloratadine, 5.0 nmol/L for fexofenadine and creased vascular permeability and vasodilatation within the nasal0.6 nmol/L for levocetirizine at a pH of 5.8. Increasing the pH to mucosa, which leads to nasal oedema and congestion. They also7.4 resulted in a binding affinity constant of 7.4 nmol/L for contribute to sneezing, pruritus, rhinorrhoea and ocular itching,levocetirizine.[41,42] Desloratadine has a higher H1 receptor affinity redness and tearing. The late-phase allergic response generallythan other second-generation antihistamines[42-46] at nearly 200 begins 2–4 hours after the early-phase response and can last for uptimes that of fexofenadine, >50 times that of loratadine and to 24 hours. During this phase, inflammatory cytokines producedcetirizine, and three times that of levocetirizine.[42,44] In an in vitro in the early-phase response stimulate adhesion of circulating leu-

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kocytes and infiltration of tissues by eosinophils, neutrophils and 10–8 mol/L) inhibited resting and granulocyte-macrophagebasophils. The activated infiltrating inflammatory cells release colony-stimulating factor (GM-CSF)-eosinophil adhesion to re-mediators that prolong and enhance the allergic cascade. combinant vascular cell adhesion molecule-1 (VCAM-1) under

flow conditions of shear stress, with a maximal effect at 10–8 mol/Pharmacological studies suggest that H1 receptor antagonistsL.[65] Other studies showed that levocetirizine inhibited ICAM-1are able to exert anti-inflammatory effects.[51] One study demon-and VCAM-1 in a dose-dependent manner in activated keratino-strated that desloratadine (1–10 µmol/L) inhibits both IgE-medi-cytes or in nasal polyp-derived fibroblasts, respectively,[66,67] andated and non-IgE-mediated generation of IL-4 and IL-13 byalso blocked GM-CSF and CCL5 release induced solely by inter-human basophils in vitro.[53] Both loratadine and desloratadineferon-γ in keratinocytes.[66]exert anti-inflammatory effects by inhibiting the release of

Although the clinical relevance of these effects, which arepreformed and de novo synthesized mediators from human FcεRI+manifested at both therapeutic and supratherapeutic concentra-cells.[54] The release of proinflammatory mediators from eosino-tions, has yet to be established conclusively,[68] they may explainphils, which are typically linked with late-phase allergic reactions,in part the efficacy of H1 receptor antagonists in relieving allergicis inhibited by desloratadine.[55,56]

symptoms. One of the mechanisms by which such anti-inflamma-At nanomolar concentrations (10–9 to 10–5 mol/L), deslorata-tory and antiallergic effects are mediated may be through inhibi-dine has been shown to inhibit endothelial expression of P-selectintion of the gene expression regulator nuclear factor-κB (NF-κB).(a surface molecule involved in the adhesion of neutrophils andThis transcription factor regulates the production of a number ofeosinophils to endothelial cells) and to reduce the expression ofproinflammatory cytokines and is activated by the H1 receptor inIL-6 and IL-8 in response to the histamine challenge.[57] Whenthe absence of histamine.[47,69] Second-generation H1 receptorpreincubated with human mast and basophilic cells, desloratadineantagonists have been shown to inhibit the basal and histamine-(10–11 to 10–5 mol/L) inhibited IL-6 release by 40% and IL-8related activity of NF-κB in the presence (but not in the absence)release by 50%.[58] Desloratadine also significantly reduced secre-of the H1 receptor.[47] The inverse agonist potency of second-tion of tumour necrosis factor-α from human leukaemic mast cellsgeneration antagonists is likely to explain the inhibition of NF-κBand basophils.[59] Although some of the concentrations investigat-activity and is related to the binding potency on H1 receptors.[69]ed were supratherapeutic, many were in the therapeutic rangeTherefore, at equivalent concentrations, the rank order of poten-(about 10–8 mol/L with respect to peak plasma concentrations) andcies is: desloratadine > cetirizine > loratadine > fexofenadine.therefore of potential clinical utility. In a randomized, double-However, even at slightly greater than therapeutically relevantblind, parallel-group study in which the leukotriene inhibitorplasma concentrations, desloratadine, fexofenadine and levoce-montelukast was added to either cetirizine or desloratadine, bothtirizine may exert anti-inflammatory activities in vitro.combinations significantly reduced IL-5 and IL-8 concentra-

tions.[60]

Fexofenadine (10–7 to 10–4 mol/L) has been shown to inhibit 2.4 CNS Effects

IL-6 release from human macrophages in a concentration-depen-dent fashion. The inhibitory effect was significant at 10–6 mol/ An important differentiating factor between antihistamines isL.[61] Fexofenadine (10–4 and 10–3 mol/L) also inhibited intercel- the degree of somnolence that patients experience. Low blood-lular adhesion molecule-1 (ICAM-1) expression.[62] At a concen- brain barrier penetration explains the relative lack of CNS effectstration of >250 ng/mL (i.e. about 5 × 10–7 mol/L), fexofenadine associated with second-generation H1 receptor antagonists, unlikeinhibited CC chemokine ligand-5 (CCL5; previously known as their first-generation counterparts.[70-72] Recent developments haveRegulated upon Activation, Normal T cell Expressed and Secreted shown that the CNS concentrations of drugs are controlled by the[RANTES]) and eotaxin produced from active nasal polyp fibro- P-glycoprotein (P-gp) transporter system, as well as lipophilicityblasts.[63] The mean peak plasma concentration of fexofenadine at and ionization.[73,74] The newer antihistamines are usually non-recommended doses is about 10–6 mol/L. sedating at the recommended doses, perhaps as a result of active

In one study, levocetirizine (10–9 to 10–7 mol/L) inhibited efflux of the drugs from the brain by P-gp (seen in P-gp transfectedeotaxin-induced eosinophil transendothelial migration (TEM) on cells and P-gp knockout mice).[71,75] Because P-gp is just one of thea dose-dependent basis in both dermal and lung microvascular many efflux transporters that may control the brain distribution ofendothelial cells. However, levocetirizine did not significantly H1 receptor antagonists, a comparison of antihistamines based onaffect spontaneous eosinophil TEM, eosinophil viability or apop- efflux transporters would be incomplete. Also, both influx andtosis induction.[64] In an in vitro model of post-capillary venules, efflux transporters are involved in the distribution of H1 receptortherapeutically relevant concentrations of levocetirizine (about antagonists in the brain and should be investigated in conjunction

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Pharmacology of New Antihistamines 221

with one another. The complexity of these mechanisms empha- (0.1%) and 46 cases (0.4%), respectively, with 50% of casessizes the need for an accurate clinical evaluation of the sedative occurring by days 7 and 14, respectively.[89] However, the time-to-properties of antihistamines. event estimates differed (log rank test, p < 0.0001). There was a 5-

fold significant increase in the odds of drowsiness/sedation inFexofenadine has no significant effect on cognitive perform-levocetirizine compared with desloratadine in the first month ofance or driving and is considered to be nonsedating.[4,76-78]

observation in the total cohort, and a 6.75-fold increase in theDesloratadine does not impair cognitive or psychomotor perform-subgroup of patients with AR but not asthma. Age, sex andance[2,79-81] or potentiate the deleterious effects of alcohol (ethanol)previous antihistamine use were not confounding factors.[89]

on psychomotor performance,[82,83] and is also nonsedating, evenat nine times its standard dose.[2,80,84,85]

3. Pharmacokinetics of H1 Receptor AntagonistsNevertheless, the newest antihistamines may still cause a smalldegree of sedation (table I).[6,7,77-82,86-93] Although levocetirizinewas found to be nonimpairing in some clinical studies,[90,91] reports 3.1 Absorption/Metabolism/Eliminationof somnolence, fatigue and asthenia in clinical trials are noted onthe label of the product.[6,7] The label cautions against engaging in The main pharmacokinetic and metabolic properties of deslo-‘potentially hazardous activities’ and includes warnings about ratadine, fexofenadine and levocetirizine are summarized in tableoperating machinery or driving a motor vehicle after levocetirizine II.[2-4,86,94-100] The pharmacokinetic parameters of H1 receptor ant-use.[6,7] In a double-blind study comparing desloratadine, levoce- agonists vary according to the chemical structure. Levocetirizinetirizine and placebo, the incidence of somnolence with these and fexofenadine undergo limited first-pass metabolism and doagents was 0.7%, 2.1% and 1.1%, respectively.[86] In the Xyzal in not have active metabolites. Levocetirizine is predominantly elim-PErsistent Rhinitis Trial (XPERT), 6.8% of subjects treated with inated via the urine, whereas fexofenadine is mainly eliminated inlevocetirizine reported somnolence versus 1.8% of those treated the faeces.[4,97,100,101] A positive aspect of poorly metabolizedwith placebo.[88] drugs is the low intersubject variability of the pharmacokinetic

parameters.A prescription-event monitoring study, described as an investi-gation of the safety of newly marketed drugs conducted under Loratadine is metabolized to the active metabolite deslorata-‘primary care conditions’, reviewed adverse-event reporting dine, which is then metabolized to 3-hydroxydesloratadine in theamong subjects receiving desloratadine or levocetirizine.[89] A liver and undergoes further metabolism by glucuronidation. Thefocus of this study was to determine whether desloratadine and enzyme pathway involved in the liver metabolism of desloratadinelevocetirizine differed in their potential to cause drowsiness and to 3-hydroxydesloratadine has not yet been reported. One studysedation. The incidence of drowsiness/somnolence for deslorata- demonstrated that the in vitro formation of 3-hydroxydeslorata-dine and levocetirizine was very low for both drugs: nine cases dine-glucuronide from 3-hydroxydesloratadine was mediated

Table I. CNS effects of desloratadine, fexofenadine and levocetirizine

Effect Desloratadine Fexofenadine Levocetirizine

Somnolence (%) 0.7[86] 0[87] 2.1–6.8[86,88]

Drowsiness/sedation (%) 0.1[89] ND 0.4[89]

Cognitive or psychomotor No impairment of driving No sedation or impairment of Both the US and the EU labels

impairment performance[79] psychomotor performance[77] recommend that patients who wish to

No sedative or performance- No impairment of driving operate machinery, drive or engage in

impairing effects[80] performance or aspects of possibly hazardous activities take their

No difference from placebo in psychomotor and cognitive function, response to levocetirizine into account

somnolence, wakefulness and even when combined with a dose before taking the drug, as some people

psychomotor performance[81] of alcohol equivalent to 0.3 g/kg of experience fatigue, asthenia or

No potentiation of alcohol (ethanol)- bodyweight[78] somnolence[6,7]

induced performance impairment[82] Some studies report a lack of significant

impairment of driving performance,[90]

psychomotor and cognitive function,[91,92]

or memory and psychomotor

performance[93]

ND = No data.

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222 Devillier et al.

Table II. Main pharmacokinetic, pharmacodynamic and metabolic properties of desloratadine, fexofenadine and levocetirizine

Property Desloratadine Fexofenadine Levocetirizine

Absorption (tmax) [h] ~3[2] 1–3[4] 0.9[7]

Onset of action (after exposure to allergens) [h] 3[2] 1–3[3,4] ~1[7]

Duration of action (h) 24[29,86] 24[29] 24[29,86]

Volume of distribution (L/kg) ~49[94] 5.4–5.8[94] 0.41[95]

Metabolites (% of dose) ND (extensive metabolism)[96] ~5[3] 14[97]

Enzymes involved in metabolism UGT1A1, 1A3, 2B15[98]

Terminal elimination half-life (h) 27[2] 11–15[4] 8[7]

Urinary excretion (% of radioactive dose) 41[99] 11[3,100] 85[97]

Faecal excretion (% of radioactive dose) 47[99] 80[3,100] 13[99]

ND = no data; tmax = time to reach maximum plasma concentration; UGT = uridine diphosphate glucuronosyltransferase.

via uridine diphosphate glucuronosyltransferase (UGT) 1A1, bo.[109] Allergen-challenge chamber studies are often used to deter-UGT1A3 and UGT2B15 in the human liver.[98] Desloratadine mine the onset of action.[109] The onset of action of desloratadineundergoes less first-pass metabolism than loratadine; therefore, or loratadine has been reported to range from 1 hour 15 minutes tothe variability in systemic exposure to desloratadine is potentially 3 hours.[86,110-113] Levocetirizine and cetirizine have a demonstra-decreased. Elimination occurs via both the renal and faecal path- ted onset of action of 45 minutes to 1 hour. In individual studies,ways.[102] the onset of action occurred sooner than with loratadine or

desloratadine.[86,110,112,114] However, in one study, no differenceThe pharmacokinetic feature classically considered for thewas observed between loratadine and cetirizine.[115] Fexofenadineevaluation of the onset of action of a drug is the time it takes toand cetirizine had comparable onsets of action in one study con-reach the peak plasma concentration (tmax). This time is shortestducted in such an environmental exposure unit.[116] Although suchfor levocetirizine (about 1 hour) and longest for desloratadinestudies are used to determine the beginning of symptom reduction,(about 3 hours), with fexofenadine falling somewhere between thethey do not mimic real-life situations, because they are conductedtwo (about 1–3 hours).[2-4,7] The tmax depends on the mechanismsin select patient populations (those with a predetermined symptomof the absorption phase and the level of intestinal and liver first-score after a priming session). Also, these studies do not reproducepass metabolisms. However, for rapidity of action, the time tothe spontaneous variations in pollen exposures that occur natural-reach a plasma concentration sufficient for an effective blockadely, and usually rely on relatively short durations of exposure andof H1 receptors at target tissue levels is much more appropriate.treatment.Some information is available on skin-tissue concentrations of

second-generation antihistamines,[103] but the limited, heterogene-3.2 Volume of Distributionous data do not allow for a comparison of tissue kinetics among

these drugs. In addition, information on the time to reach plasmaHuman data on drug concentrations in targeted tissues are

therapeutic concentrations (i.e. free plasma concentrations suffi-generally lacking, but comparative information on the rate and

cient to block H1 receptors) is scarce.extent of drug distribution in humans can be derived from observa-

The onset of action of antihistaminic activity can also be tions in plasma. The plasma concentration is the result of the doseevaluated through the inhibitory effects on histamine-induced skin administered after complete body distribution. At equilibrium, thewheal-and-flare responses. The time to reach maximal inhibition extent of distribution is defined by the apparent volume of distri-of wheals was 4 hours for desloratadine, fexofenadine and levoce- bution (Vd) [the fluid volume required to contain the drug in thetirizine.[104-106] However, histamine-induced wheal-and-flare re- body at the same concentration as in plasma]. This parametersponses are not correlated with clinical efficacy in AR or CIU and provides a reference for the plasma concentration expected for aare therefore not appropriate surrogate markers with which to given dose, and for the dose required to produce a given concentra-compare antihistamines.[107,108]

tion. However, it provides little information about the specificThe US FDA has defined the onset of action as the first pattern of distribution, as each drug is uniquely distributed in the

timepoint after initiation of treatment when the study drug demon- body. Some drugs enter fat cells, some remain in the extracellularstrates a change from baseline in the primary efficacy endpoint fluid, and others are bound to specific tissues, commonly those inthat is statistically significantly greater than that seen with place- the liver or kidney; therefore, a low Vd does not necessarily imply

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Pharmacology of New Antihistamines 223

a lowered risk of toxicity or greater efficacy. A high Vd does not ministration of P-gp inhibitors (e.g. ketoconazole, azithromycin,always indicate greater toxicity, as this occurs only in tissues erythromycin and itraconazole) or inducers (e.g. rifampicin [ri-containing drug-activated receptors involved in cellular toxici- fampin]).[94] Changes are more frequently reported with fex-ty.[117,118] For example, desloratadine, with a Vd higher (~49 L/kg) ofenadine; specifically, coadministration of ketoconazole or ery-than that of fexofenadine (5.4–5.8 L/kg) and cetirizine/levoce- thromycin has been shown to enhance the gastrointestinal absorp-tirizine (0.4 L/kg),[94] has no cardiovascular effects at up to nine tion of fexofenadine.[4] One study reported a significant increasetimes its clinical dose.[85] Thus, the Vd by itself cannot be used as a (p < 0.05) in the maximum plasma concentration (Cmax) of fex-reliable marker of toxicity or efficacy.[117] ofenadine and a significant decrease (p < 0.05) in oral clearance

following a single dose of St John’s wort (hypericum). The effects3.3 Duration of Action and Potency are consistent with inhibition of intestinal wall P-gp activity and an

increase in fexofenadine bioavailability.[123] Long-term adminis-When assessing the duration of action and the potency of

tration was associated with significantly reduced (p < 0.05) plas-antihistamines, the wheal-and-flare response test is frequently

ma concentrations of fexofenadine and a significant increaserepresented as a measure of clinical efficacy. However, it is a

(p < 0.05) in oral clearance of the antihistamine. These effectsquestionable measure of efficacy,[108] as results from this test

were consistent with an induction of P-gp and reduced fex-(usually performed in healthy volunteers) frequently do not corre-

ofenadine bioavailability.[123] In one study, single doses of ritona-late with clinically derived endpoints, and measurement of the

vir or a combination of ritonavir plus lopinavir increased exposureresponse to histamine in the skin does not always compare with the

to fexofenadine by 2.2- and 4.0-fold, respectively, whereas steady-results in other tissues. For example, in a study comparing

state ritonavir plus lopinavir increased fexofenadine exposure bydesloratadine with levocetirizine,[119] no differences were found in

2.9-fold. This effect decreased with repeated dosing but remainedclinical endpoint measures between the two medications, despite

present and was suggested to be the result of P-gp inhibition bythe fact that levocetirizine demonstrated better suppression of the

ritonavir plus lopinavir.[124] Despite these effects, no fexofenadinewheal-and-flare response.

dosage adjustments are recommended.The terminal elimination half-life (t1/2) can be used as an alter-

It should be noted that these drugs also interact with othernative measure of duration of action. The t1/2 of desloratadine is

transporters and/or drug-metabolizing enzymes, mainly cyto-approximately 27 hours, compared with 11–15 hours for fex-

chrome P450 (CYP) 3A4. Fexofenadine is a substrate of OATPofenadine and 8 hours for levocetirizine.[2,4,7] Again, plasma con-

(particularly OATP1A2), whereas desloratadine is not.[121,125,126]

centrations are not correlated with concentrations in targeted tis-Grapefruit, apple and orange juice interfere with P-gp/OATP

sues,[103] making it difficult to estimate the duration of action basedactivity.[125] Studies comparing the effects of coadministering

on the plasma t1/2.either desloratadine or fexofenadine with grapefruit juice foundthe pharmacokinetics of desloratadine to be essentially un-4. Drug-Drug Interactionschanged, and the bioavailability of fexofenadine decreased by30–52%.[126,127] Coadministration of desloratadine with food or

4.1 Interactions via Active Drug Transporters antacids does not affect its absorption.[2,94] No drug-drug inter-action studies have been conducted with levocetirizine.[7]

Active drug transport molecules, such as P-gp and the organicanion transporting polypeptide (OATP) family, play an importantrole in the absorption, tissue distribution and excretion of drugs. P- 4.2 Interactions via Cytochrome P450

gp is an efflux pump that is highly expressed in the gut, liver,kidney and brain. It contributes to a decreased penetration of In vitro, desloratadine caused no significant inhibition of majorsubstrate xenobiotics in the brain and decreased absorption of CYP isoenzymes, including CYP1A2, CYP2C9, CYP2C19,these xenobiotics in the gut.[94] Conversely, OATPs are uptake CYP2D6 and CYP3A4.[128] In pharmacokinetic and clinical trials,transporters facilitating intestinal absorption of substrate xenobiot- desloratadine was coadministered with numerous CYP3A4 andics or tissue penetration.[120] Gut P-gp activity is saturated by high CYP2D6 inhibitors (specifically, erythromycin, ketoconazole,concentrations of drug substrates in the intestine and is therefore azithromycin, cimetidine and fluoxetine), with no effects on clini-unlikely to be important in overall drug absorption. cally relevant parameters.[2,129-133]

Desloratadine, fexofenadine and levocetirizine are not consid- When some antihistamines are coadministered with medica-ered to be significant P-gp inhibitors.[94,121,122] However, the plas- tions that compete for CYP, abnormally high drug concentrationsma pharmacokinetics of desloratadine are weakly altered by coad- in the bloodstream and tissues may result in negative clinical

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224 Devillier et al.

effects. For example, coadministration of fexofenadine with ery- 5. Use of Desloratadine and Other

Second-Generation H1 Receptor Antagoniststhromycin[134] or ketoconazole[4,135] led to an increase in fex-in Special Patient Subpopulationsofenadine concentrations, although no differences in adverse

events or corrected QT intervals were reported.[4] Even at concen-

trations well above the Cmax achieved within therapeutic dose 5.1 Age/Sex

ranges, levocetirizine does not inhibit CYP isoenzymes 1A2, 2C9,The clinical efficacy and safety of desloratadine was evaluated2C19, 2D6, 2E1 and 3A4, and does not induce UGTIA or CYP

in >2300 patients aged 12–75 years with SAR. A total of 1838isoenzymes 1A2, 2C9 and 3A4.[7]

patients received 2.5–20 mg/day of desloratadine in four random-Although no interaction studies have been performed with ized, double-blind, placebo-controlled clinical trials of 2–4 weeks’

levocetirizine, the pharmacokinetics of cetirizine were not altered duration conducted in the US.[1] The mean Cmax and AUC valuesby concomitant administration of azithromycin, cimetidine, ery- for desloratadine following multiple-dose administration werethromycin, ketoconazole or theophylline.[7] A 42% increase in the 20% greater in younger subjects (aged <65 years) than in older

subjects (aged ≥65 years). The apparent oral clearance, whenarea under the plasma concentration-time curve (AUC) and a 53%normalized for bodyweight, was similar between the two ageincrease in the cetirizine t1/2 were observed after concomitantgroups. The mean t1/2 of desloratadine was 33.7 hours in subjectsadministration of ritonavir.[136] In addition, cetirizine does notaged ≥65 years.[1] The pharmacokinetics for 3-hydroxydeslorata-significantly alter the pharmacokinetics of erythromycin, ketoco-dine (3-OH desloratadine) appeared to be unchanged in oldernazole, theophylline, ritonavir or alcohol.[7,94,136]

versus younger subjects. Although age-related differences havebeen observed, they are not clinically relevant, and no dosage

4.3 Possible Interactions via Renal Transporters adjustment is required in elderly patients.[1,2]

Age-related differences have also been seen with fexofenadine.Cetirizine has been reported to interact with the class IC antiar- In patients aged ≥65 years, plasma concentrations of the drug were

rhythmic drug pilsicainide in an elderly woman with renal insuffi- 99% greater than those found in younger patients.[3] Both the USand the EU labels recommend special care and dose monitoringciency, who experienced near syncope.[137] Although the mecha-when administering fexofenadine to elderly patients.[3,4] Althoughnism of excretion of the two drugs is not fully understood, both areno specific differences in the response to levocetirizine in patientsexcreted in the urine, and competitive inhibition of renal transport-aged ≥65 years have been reported, the US label recommendsers multidrug resistant protein 1 or organic cation transporter 2 (orstarting these patients at lower dosages.[6] The EU label advisesboth) may have caused the reaction in this particular patient.dosage adjustment in the elderly only if they have moderate-to-

Whereas cetirizine was not toxic in itself, the interaction in thissevere renal impairment.[7]

case of renal failure was enough to produce toxic concentrations ofTwo recently published papers provided information on the

pilsicainide. Indeed, an increase in the QRS interval was attributed pharmacokinetics of desloratadine in paediatric populations. In amainly to high concentrations of pilsicainide rather than cetirizine. phase I, single-dose, open-label, dose-selection study, 58 childrenThe authors surmised that the increased cetirizine concentration on aged 6 months to 2 years were randomized to receive eithercoadministration may have affected the ECG abnormalities.[137] 0.625 mg (1.25 mL) or 1.25 mg (2.5 mL) of desloratadine syr-They also noted that the ECG abnormality in this case was up.[139] The apparent clearance rates of desloratadine were 27.8 L/h

(coefficient of variation [CV] 35%) in children aged ≥6 months tosomewhat similar to what was reported in another case of pilsicai-<1 year and 35.5 L/h (CV 51%) in those aged ≥1 year to ≤2 years.nide overdosage.[138] When pilsicainide was withdrawn, cetirizineThe corresponding rate in adults was 137 L/h (CV 58%).[139] Theblood concentrations returned to normal.[137]

slower clearance rates in children suggested that doses of 1 mg inThe potential for a similar interaction by the enantiomers of

subjects aged ≥6 months to <1 year and 1.25 mg in those aged ≥1cetirizine, such as levocetirizine, remains to be studied, although

year to ≤2 years would produce similar systemic exposure (asthe lower renal clearance of levocetirizine, compared with the measured by the Cmax and AUC) to that observed in adults treateddistomer (inactive/less active enantiomer) of cetirizine,[95] sug- with a 5 mg dose (the 0.625 mg dose was found to be subop-gests that the mechanism of the cetirizine-pilsicainide interaction timal).[139] In two open-label, single-dose studies in children agedmay be transferable to levocetirizine. As noted previously, no 2–5 years given 1.25 mg (2.5 mL) of desloratadine syrup (n = 18)interaction studies have been conducted with this agent.[7] and in children aged 6–11 years given 2.5 mg (5 mL) [n = 18], the

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Pharmacology of New Antihistamines 225

desloratadine Cmax was observed at a mean of ~2 hours postdose 5.2 Renal Impairment

in both age groups. The median values were 2.28 ng/mL in theDesloratadine pharmacokinetics following a single dose of

younger age group and 2.05 ng/mL in the older age group.[140]

7.5 mg were characterized in subjects with mild (n = 7; creatinineExposure to desloratadine was similar in the younger and older age clearance [CLCR] 51–69 mL/min/1.73 m2), moderate (n = 6; CLCRgroups, with median AUC values at the time of the last quantifi- 34–43 mL/min/1.73 m2) and severe (n = 6; CLCR 5–29 mL/min/able sample of 38.8 and 38.2 ng • h/mL, respectively. These values 1.73 m2) renal impairment or haemodialysis-dependent subjectswere similar to those observed in adults receiving 5 mg of (n = 6).[1] In subjects with mild or moderate renal impairment, thedesloratadine in syrup (35.3 ng • h/mL) or tablet form (38.5 ng • h/ median Cmax and AUC values increased by approximately 1.2-

and 1.9-fold, respectively, relative to subjects with normal renalmL).[140]

function.[1] In subjects with severe renal impairment, or in thoseThe pharmacokinetics of fexofenadine in children with a meanwho were haemodialysis dependent, the Cmax and AUC values ofage of 9.8 ± 1.8 years have also been studied.[141] The maximumdesloratadine increased by approximately 1.7- and 2.5-fold, re-

plasma concentrations were 178 ± 22 ng/mL with a single 30 mgspectively. Minimal changes in 3-OH desloratadine concentrations

dose and 286 ± 34 ng/mL with a single 60 mg dose, occurring at were observed. Desloratadine and 3-OH desloratadine were poorly2.4 hours after the medications were given. The mean clearance removed by haemodialysis. Plasma protein binding of deslorata-rates and t1/2 values with the two dosages were not significantly dine and 3-OH desloratadine was unaltered by renal impairment.[1]

different (p > 0.05). These pharmacokinetic findings were similar Although the US label for desloratadine recommends adjusting theto what was previously reported in adults.[141] In a population dosage for patients with renal impairment,[1] the EU label advises

caution in the case of severe renal insufficiency.[2]pharmacokinetic analysis of data, the apparent oral clearanceIn subjects with mild-to-moderate (CLCR 41–80 mL/min) andestimates for fexofenadine averaged 36% lower in subjects aged

severe (CLCR 11–40 mL/min) renal impairment, peak plasma2–5 years and 44% lower in those aged 6–12 years compared withconcentrations of fexofenadine were 87% and 111% greater, re-adults.[3]

spectively, and the mean t1/2 was 59% and 72% longer, respective-In children aged 12–24 months, the pharmacokinetic/pharma-

ly, than those observed in subjects with normal renal function.codynamic profile of levocetirizine 0.125 mg/kg twice daily was Peak plasma concentrations in subjects on dialysis (CLCR ≤10 mL/deemed to be “adequate”, based on a peak plasma concentration of min) were 82% higher and the t1/2 was 31% longer than those286 ± 68 ng/mL after 1 hour, a t1/2 of 4.1 ± 0.7 hours, a body observed in normal subjects.[3] Based on increases in bioavailabil-clearance of 1.05 ± 0.10 mL/min/kg and a Vd of 0.37 ± 0.06 L/ ity and the t1/2, the US label recommends a dose of 60 mg oncekg.[142] In the Early Treatment of the Atopic Child (ETAC) study, daily as the starting dosage in patients with decreased renal func-

tion,[3] though the EU label states that fexofenadine should bewhich enrolled children aged 14–46 months, the rate of the in-administered with care in this group.[4]crease in levocetirizine clearance with age or bodyweight was

The apparent total body clearance of levocetirizine is correlatedslower than the rate of the increase in the Vd with the same factors.with the CLCR. Therefore, both the US and EU labels suggest thatThe investigators therefore predicted that the oral clearance rate ofthe dosing intervals be adjusted based on CLCR in patients withlevocetirizine increases with age and bodyweight. This suggestsmoderate and severe renal impairment. Levocetirizine is contrain-

that relatively high doses and/or twice-daily dosing may be re-dicated in subjects with end-stage renal disease,[6,7] because of its

quired in very young children, as has been reported with ce-major elimination by renal excretion. In subjects with anuric end-

tirizine.[143] For children aged 6–11 years, once-daily dosing may stage renal disease, the total body clearance is decreased by aboutbe optimal, based on a mean t1/2 of 5.7 ± 0.2 hours, a peak 80% when compared with normal subjects. The amount of levoce-concentration of 450 ± 37 ng/mL at 1.2 ± 0.2 hours, an oral tirizine removed during a standard 4-hour haemodialysis proce-clearance of 0.82 ± 0.05 mL/min/kg and a Vd of 0.4 ± 0.02 L/ dure was <10%.[7]

kg.[144]

5.3 Hepatic ImpairmentAlthough the Cmax and AUC values with desloratadine and 3-

OH desloratadine were higher in females than in males, no clinical Subjects with hepatic impairment (n = 12), regardless of severi-relevance that requires dosage adjustment has been demonstra- ty, who were administered desloratadine had approximately ated.[145] For fexofenadine and levocetirizine, no clinically signif- 2.4-fold increase in the AUC as compared with subjects withicant sex-related differences have been observed.[3,6] normal hepatic function.[1] The apparent oral clearance of

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226 Devillier et al.

desloratadine in subjects with mild, moderate and severe hepatic addition, desloratadine, fexofenadine and levocetirizine have anti-impairment was 37%, 36% and 28% of that in normal subjects, inflammatory effects in vitro at concentrations similar to plasmarespectively. An increase in the mean t1/2 of desloratadine in concentrations seen with therapeutic use, which may be clinicallysubjects with hepatic impairment was observed. For 3-OH relevant.desloratadine, the mean Cmax and AUC values for subjects with Desloratadine and fexofenadine do not impair cognitive orhepatic impairment were not statistically significantly different motor performance and have somnolence rates comparable withfrom those in subjects with normal hepatic function.[1] In a phase I, placebo. Mixed results for CNS effects have been reported withopen-label, multiple-dose study of desloratadine 5 mg, increases in levocetirizine. In some studies, no cognitive or psychomotor im-the Cmax and AUC were observed in subjects with moderate pairment was demonstrated, whereas others reported somnolence,hepatic impairment, consistent with findings from single-dose fatigue and asthenia. The label includes warnings about operatingstudies.[1,146] When factors such as race and metabolizer status machinery or driving after using the product.were eliminated, the median exposure to desloratadine in subjects No major CYP inhibition has been reported with desloratadine.with hepatic impairment was about 3-fold greater than in subjects The bioavailability of desloratadine is weakly affected by drugswith normal liver function.[146] On the US desloratadine label, interfering with transporter molecules and/or CYPs. More fre-dosage adjustment is recommended for patients with hepatic im- quent interactions are reported with fexofenadine; however, nopairment;[1] no adjustments are mentioned on the EU label.[2] No dosage adjustments are recommended. The bioavailability of fex-differences in the absorption and elimination of fexofenadine have ofenadine is also greatly decreased by grapefruit juice, which is anbeen noted in patients with hepatic disease versus that seen in interaction not seen with desloratadine. No in vivo drug-drughealthy subjects,[3,4,147] and no dosage adjustments of levoce- interaction studies have been performed with levocetirizine.tirizine are needed.[7] No dosage adjustment based on sex is required with any of the

three agents, but dosage adjustments are needed in elderly patients5.4 Poor Metabolizers taking fexofenadine or levocetirizine. Dosage adjustments for

patients with renal impairment are recommended for all threePhenotypic polymorphism in the metabolism of desloratadine

medications.has been observed in those individuals with a decreased ability to

When selecting a second-generation antihistamine for the treat-form 3-OH desloratadine, the major metabolite of desloratadine.

ment of AR and CIU, the pharmacological characteristics shouldSuch individuals are termed ‘poor metabolizers of deslorata-

be taken into account. H1 receptor binding affinity, CNS effectsdine’.[148] The prevalence of the poor metabolizer phenotype in the

and pharmacokinetic, pharmacodynamic and metabolic propertiesgeneral population is approximately 6%; however, the prevalence

all provide insight into the efficacy and safety profile of each drug.among African Americans is 17% higher than that of any other

Given the similar efficacy of the newer second-generation antihis-population subgroup. The increased exposure in poor metabolizers

tamines, the lack of sedative effects and psychomotor impairmentis independent of age when administered at age-appropriate doses

and the significant interaction with drug transporter moleculesand is not associated with any changes in the safety and tolerability

may provide some advantages for the overall profile ofprofile of desloratadine.[148] There have been no published studies

desloratadine compared with fexofenadine and levocetirizine.of possible poor metabolizers of either fexofenadine and levoce-tirizine. Acknowledgements

The authors have received no funds for their involvement in this work.6. ConclusionOver the last 3 years, Dr Devillier has received fees as a consultant or speakerfor Altana Pharma AG, AstraZeneca Pharmaceuticals LP, Bioproject Pharma,The pharmacological characteristics of second-generation H1Boehringer Ingelheim GmbH, Chiesi SA France, GlaxoSmithKline, Merckreceptor antagonists differentiate them from first-generationSharp & Dohme Ltd, Sanofi-Aventis and Schering-Plough Corporation.

agents. Second-generation antihistamines are highly selective for Dr Roche has received fees as a consultant or speaker for Altana Pharma AG,the H1 receptor and bind to it with high affinity, have limited CNS AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim GmbH, Chiesi SA

France and GlaxoSmithKline. The authors have no conflicts of interest that arepenetration and are generally free from drug-drug interactions.directly relevant to the content of this review.However, even among second-generation antihistamines such as

desloratadine, fexofenadine and levocetirizine, there exist clinical-Referencesly significant pharmacological differences.

1. Clarinex [prescribing information]. Kenilworth (NJ): Schering-Plough Corpora-Of the second-generation antihistamines, desloratadine has tion, 2005

been shown to have the highest H1 receptor binding affinity. In 2. Aerius [prescribing information]. Brussels: Schering-Plough Europe, 2006

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Pharmacology of New Antihistamines 227

3. Allegra [prescribing information]. Bridgewater (NJ): Sanofi-Aventis US, LLC, 28. Dunford PJ, Williams KN, Desai PJ, et al. Histamine H4 receptor antagonists are2007 superior to traditional antihistamines in the attenuation of experimental pruri-

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