Relevance of H1-receptor occupancy to H1-antihistamine dosing in children
2007; Elsevier BV; Volume: 119; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2007.02.048
ISSN1097-6825
AutoresKeith J. Simons, M. Strolin Benedetti, F. Estelle R. Simons, Michel Gillard, Eugène Baltes,
Tópico(s)Drug-Induced Adverse Reactions
ResumoTo the Editor:The H1-histamine receptor is, like all known types of histamine receptors, a heptahelical transmembrane molecule that transduces extracellular signals to intracellular second messenger systems by way of G proteins. Like other histamine receptors, it has constitutive activity, which is defined as the ability to trigger downstream events in acute and chronic allergic inflammation, even in the absence of ligand binding. The inactive and active states of the H1-receptors exist in equilibrium. H1-antihistamines act as inverse agonists that combine with the H1-receptor, stabilizing it in the inactive form and shifting the equilibrium toward the inactive state.1Leurs R. Church M.K. Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.Clin Exp Allergy. 2002; 32: 489-498Crossref PubMed Scopus (383) Google Scholar, 2Akdis C.A. Simons F.E.R. Histamine receptors are hot in immunopharmacology.Eur J Pharmacol. 2006; 533: 69-76Crossref PubMed Scopus (205) Google ScholarFor most of the second-generation, relatively nonsedating H1-antihistamines, despite faster clearance rates and shorter terminal elimination half-life values reported in the pediatric population, the dose interval recommended for children is identical to the dose interval recommended for adults.3Simons F.E.R. Advances in H1-antihistamines.N Engl J Med. 2004; 351: 2203-2217Crossref PubMed Scopus (567) Google Scholar, 4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 5Baltes E. Coupez R. Giezek H. Voss G. Meyerhoff C. Strolin Benedetti M. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers.Fundam Clin Pharmacol. 2001; 15: 269-277Crossref PubMed Scopus (77) Google Scholar These recommendations are based on traditional pharmacodynamic studies involving measurement of H1-antihistamine–induced suppression of the histamine-induced wheal-and-flare response over time. A novel approach is to calculate H1-antihistamine occupancies at H1-receptor sites by using receptor binding constants and unbound (free) H1-antihistamine plasma concentrations (ie, the fraction of medication not bound to plasma proteins) and to correlate these values with the pharmacodynamic response.6Gillard M. Vanderperren C. Moguilevsky N. Massingham R. Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: Contribution of Lys(191) and Thr(194).Mol Pharmacol. 2002; 61: 391-399Crossref PubMed Scopus (210) Google Scholar, 7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google Scholar, 8Bree F. Thiault L. Gautiers G. Benedetti M.S. Baltes E. Rihoux J.-P. et al.Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.Fundam Clin Pharmacol. 2002; 16: 471-478Crossref PubMed Scopus (23) Google ScholarUsing this approach, we studied levocetirizine, the active enantiomer of the racemic piperazine H1-antihistamine cetirizine, which is widely used in Europe in children and adults with allergic rhinitis or urticaria and is currently an investigational drug in North America. We hypothesized that levocetirizine H1-receptor occupancy in children 6 to 11 years of age after a 5-mg oral dose would be similar to levocetirizine H1-receptor occupancy in adults after this dose. Our objective was to calculate H1-receptor occupancy by levocetirizine and use these data to predict the onset and duration of suppression of the histamine-induced wheal-and-flare response after the administration of a 5-mg levocetirizine dose in children.The pharmacokinetics of levocetirizine in children 6 to 11 years of age have been previously described after administration of a single 5-mg dose.4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Peak plasma concentrations of 450 ± 37 ng/mL (± SEM) occur at 1.2 ± 0.2 hours. The oral clearance is 0.82 ± 0.05 mL · kg · min−1, and the apparent volume of distribution, 0.4 ± 0.02 L/kg, is small. The terminal elimination half-life is 5.7 ± 0.2 hours, and the mean residence time is 6.8 ± 0.3 hours. Based on these pharmacokinetic parameters, and considering that in adults oral levocetirizine clearance is slower (0.62 ± 0.002 mL · kg · min−1 [± SEM]) and the terminal elimination half-life is longer (7.8 ± 0.3 hours),5Baltes E. Coupez R. Giezek H. Voss G. Meyerhoff C. Strolin Benedetti M. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers.Fundam Clin Pharmacol. 2001; 15: 269-277Crossref PubMed Scopus (77) Google Scholar twice-daily dosing might appear to be optimal for children in this age range.It has been found in a pediatric pharmacodynamic study, however, that after a 5-mg dose of levocetirizine, histamine-induced wheal-and-flare responses were suppressed (P < .05) from 1 to 28 hours, with maximal suppression of wheals (97% ± 1%) from 2 to 10 hours and maximal suppression of flares (93% ± 1%) from 2 to 24 hours.4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarEstimating the in vivo receptor occupancy might provide additional data to confirm the observed pharmacodynamic response and to establish this response as a better predictor of optimal H1-antihistamine pediatric dose regimens than are clearance rates and terminal elimination half-life values. Therefore by using the unbound (free) levocetirizine plasma concentrations and in vitro affinity data, medication concentrations at receptor sites were calculated, and the kinetics of wheal-and-flare suppression were compared with the kinetics of receptor occupancy.7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google ScholarThe percentage of the H1-histamine receptors occupied by levocetirizine was calculated at each time after dosing by using the following equation6Gillard M. Vanderperren C. Moguilevsky N. Massingham R. Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: Contribution of Lys(191) and Thr(194).Mol Pharmacol. 2002; 61: 391-399Crossref PubMed Scopus (210) Google Scholar, 7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google Scholar:RO(%)=100%×([L]/([L]+Ki))×(1−e−((kon×[L])+koff)×t),where RO is defined as receptor occupancy, [L] is defined as unbound (free) concentration of levocetirizine, Ki is defined as affinity of levocetirizine for the H1-histamine receptor, and kon and koff are the association and dissociation constants for levocetirizine. The values used in calculations were as follows: levocetirizine unbound (free) fraction = 0.0879; kinetic kon = 2.3 min−1X 1 X μmol−1; koff = 0.005 min−1; and koff/kon = Ki = 3 nmol/L (equilibrium Kd = 3 nmol/L).After a 5-mg dose, unbound (free) levocetirizine concentrations were 50 ± 4 nmol/L at 4 hours and 5 ± 1 nmol/L at 24 hours compared with 28 nmol/L at 4 hours and 4 nmol/L at 24 hours in adults. Levocetirizine H1-receptor occupancies at 4 and 24 hours were 94% ± 0.4% and 60% ± 3% compared with values of 90% and 57%, respectively, in adults.Percentage of wheal suppression versus levocetirizine unbound (free) plasma concentrations compared with percentage of wheal suppression versus levocetirizine H1-receptor occupancy is shown in Fig 1. Percentage of flare suppression versus levocetirizine unbound (free) plasma concentrations compared with percentage of flare suppression versus levocetirizine H1-receptor occupancy is shown in Fig 2. When the percentage of suppression of wheal-and-flare responses is plotted versus the percentage of H1-receptor occupancy by levocetirizine, the counterclockwise loop of hysteresis is reduced, corroborating the hypothesis that the kinetics of receptor occupancy are a better representative of the time course of pharmacodynamics than are the plasma pharmacokinetics.Fig 2A, Suppression of histamine-induced flare versus levocetirizine unbound (free) plasma concentrations. B, Suppression of histamine-induced flare versus levocetirizine H1-receptor occupancy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The H1-receptor occupancy data therefore provide additional pharmacodynamic support for the appropriateness of once-daily levocetirizine dosing in children age 6 to 11 years,4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar as is recommended for adults,8Bree F. Thiault L. Gautiers G. Benedetti M.S. Baltes E. Rihoux J.-P. et al.Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.Fundam Clin Pharmacol. 2002; 16: 471-478Crossref PubMed Scopus (23) Google Scholar despite faster clearance and shorter terminal elimination half-life values in the pediatric age group. To the Editor: The H1-histamine receptor is, like all known types of histamine receptors, a heptahelical transmembrane molecule that transduces extracellular signals to intracellular second messenger systems by way of G proteins. Like other histamine receptors, it has constitutive activity, which is defined as the ability to trigger downstream events in acute and chronic allergic inflammation, even in the absence of ligand binding. The inactive and active states of the H1-receptors exist in equilibrium. H1-antihistamines act as inverse agonists that combine with the H1-receptor, stabilizing it in the inactive form and shifting the equilibrium toward the inactive state.1Leurs R. Church M.K. Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.Clin Exp Allergy. 2002; 32: 489-498Crossref PubMed Scopus (383) Google Scholar, 2Akdis C.A. Simons F.E.R. Histamine receptors are hot in immunopharmacology.Eur J Pharmacol. 2006; 533: 69-76Crossref PubMed Scopus (205) Google Scholar For most of the second-generation, relatively nonsedating H1-antihistamines, despite faster clearance rates and shorter terminal elimination half-life values reported in the pediatric population, the dose interval recommended for children is identical to the dose interval recommended for adults.3Simons F.E.R. Advances in H1-antihistamines.N Engl J Med. 2004; 351: 2203-2217Crossref PubMed Scopus (567) Google Scholar, 4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 5Baltes E. Coupez R. Giezek H. Voss G. Meyerhoff C. Strolin Benedetti M. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers.Fundam Clin Pharmacol. 2001; 15: 269-277Crossref PubMed Scopus (77) Google Scholar These recommendations are based on traditional pharmacodynamic studies involving measurement of H1-antihistamine–induced suppression of the histamine-induced wheal-and-flare response over time. A novel approach is to calculate H1-antihistamine occupancies at H1-receptor sites by using receptor binding constants and unbound (free) H1-antihistamine plasma concentrations (ie, the fraction of medication not bound to plasma proteins) and to correlate these values with the pharmacodynamic response.6Gillard M. Vanderperren C. Moguilevsky N. Massingham R. Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: Contribution of Lys(191) and Thr(194).Mol Pharmacol. 2002; 61: 391-399Crossref PubMed Scopus (210) Google Scholar, 7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google Scholar, 8Bree F. Thiault L. Gautiers G. Benedetti M.S. Baltes E. Rihoux J.-P. et al.Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.Fundam Clin Pharmacol. 2002; 16: 471-478Crossref PubMed Scopus (23) Google Scholar Using this approach, we studied levocetirizine, the active enantiomer of the racemic piperazine H1-antihistamine cetirizine, which is widely used in Europe in children and adults with allergic rhinitis or urticaria and is currently an investigational drug in North America. We hypothesized that levocetirizine H1-receptor occupancy in children 6 to 11 years of age after a 5-mg oral dose would be similar to levocetirizine H1-receptor occupancy in adults after this dose. Our objective was to calculate H1-receptor occupancy by levocetirizine and use these data to predict the onset and duration of suppression of the histamine-induced wheal-and-flare response after the administration of a 5-mg levocetirizine dose in children. The pharmacokinetics of levocetirizine in children 6 to 11 years of age have been previously described after administration of a single 5-mg dose.4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Peak plasma concentrations of 450 ± 37 ng/mL (± SEM) occur at 1.2 ± 0.2 hours. The oral clearance is 0.82 ± 0.05 mL · kg · min−1, and the apparent volume of distribution, 0.4 ± 0.02 L/kg, is small. The terminal elimination half-life is 5.7 ± 0.2 hours, and the mean residence time is 6.8 ± 0.3 hours. Based on these pharmacokinetic parameters, and considering that in adults oral levocetirizine clearance is slower (0.62 ± 0.002 mL · kg · min−1 [± SEM]) and the terminal elimination half-life is longer (7.8 ± 0.3 hours),5Baltes E. Coupez R. Giezek H. Voss G. Meyerhoff C. Strolin Benedetti M. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers.Fundam Clin Pharmacol. 2001; 15: 269-277Crossref PubMed Scopus (77) Google Scholar twice-daily dosing might appear to be optimal for children in this age range. It has been found in a pediatric pharmacodynamic study, however, that after a 5-mg dose of levocetirizine, histamine-induced wheal-and-flare responses were suppressed (P < .05) from 1 to 28 hours, with maximal suppression of wheals (97% ± 1%) from 2 to 10 hours and maximal suppression of flares (93% ± 1%) from 2 to 24 hours.4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Estimating the in vivo receptor occupancy might provide additional data to confirm the observed pharmacodynamic response and to establish this response as a better predictor of optimal H1-antihistamine pediatric dose regimens than are clearance rates and terminal elimination half-life values. Therefore by using the unbound (free) levocetirizine plasma concentrations and in vitro affinity data, medication concentrations at receptor sites were calculated, and the kinetics of wheal-and-flare suppression were compared with the kinetics of receptor occupancy.7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google Scholar The percentage of the H1-histamine receptors occupied by levocetirizine was calculated at each time after dosing by using the following equation6Gillard M. Vanderperren C. Moguilevsky N. Massingham R. Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: Contribution of Lys(191) and Thr(194).Mol Pharmacol. 2002; 61: 391-399Crossref PubMed Scopus (210) Google Scholar, 7Gillard M. Strolin Benedetti M. Chatelain P. Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.Inflamm Res. 2005; 54: 367-369Crossref PubMed Scopus (50) Google Scholar:RO(%)=100%×([L]/([L]+Ki))×(1−e−((kon×[L])+koff)×t),where RO is defined as receptor occupancy, [L] is defined as unbound (free) concentration of levocetirizine, Ki is defined as affinity of levocetirizine for the H1-histamine receptor, and kon and koff are the association and dissociation constants for levocetirizine. The values used in calculations were as follows: levocetirizine unbound (free) fraction = 0.0879; kinetic kon = 2.3 min−1X 1 X μmol−1; koff = 0.005 min−1; and koff/kon = Ki = 3 nmol/L (equilibrium Kd = 3 nmol/L). After a 5-mg dose, unbound (free) levocetirizine concentrations were 50 ± 4 nmol/L at 4 hours and 5 ± 1 nmol/L at 24 hours compared with 28 nmol/L at 4 hours and 4 nmol/L at 24 hours in adults. Levocetirizine H1-receptor occupancies at 4 and 24 hours were 94% ± 0.4% and 60% ± 3% compared with values of 90% and 57%, respectively, in adults. Percentage of wheal suppression versus levocetirizine unbound (free) plasma concentrations compared with percentage of wheal suppression versus levocetirizine H1-receptor occupancy is shown in Fig 1. Percentage of flare suppression versus levocetirizine unbound (free) plasma concentrations compared with percentage of flare suppression versus levocetirizine H1-receptor occupancy is shown in Fig 2. When the percentage of suppression of wheal-and-flare responses is plotted versus the percentage of H1-receptor occupancy by levocetirizine, the counterclockwise loop of hysteresis is reduced, corroborating the hypothesis that the kinetics of receptor occupancy are a better representative of the time course of pharmacodynamics than are the plasma pharmacokinetics. The H1-receptor occupancy data therefore provide additional pharmacodynamic support for the appropriateness of once-daily levocetirizine dosing in children age 6 to 11 years,4Simons F.E.R. Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years.J Allergy Clin Immunol. 2005; 116: 355-361Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar as is recommended for adults,8Bree F. Thiault L. Gautiers G. Benedetti M.S. Baltes E. Rihoux J.-P. et al.Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.Fundam Clin Pharmacol. 2002; 16: 471-478Crossref PubMed Scopus (23) Google Scholar despite faster clearance and shorter terminal elimination half-life values in the pediatric age group.
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