Clinical Pharmacology: Advances and Applications Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Rupatadine Oral Solution Titration by Body Weight in Paediatric Patients Suffering from Allergic Rhinitis: A Population Pharmacokinetic Study Eva Santamaria 1,2 Background: Allergic rhinitis (AR) and chronic urticaria, both are treated in children with Iñaki Izquierdo 2 doses of second generation of antihistamines that have been mostly based on extrapolation of Marta Valle 1,3 data obtained in adults. The objectives of this work were to develop a model to explain the 1 pharmacokinetics (PK) of rupatadine, a second generation antihistamine, administered to chil­ Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat dren 2−11 years old and to calculate the non-compartmental PK parameters for two groups of age Autònoma de Barcelona, Barcelona, (2–5 and 6–11 years old) based on the individual Bayesian estimates from the selected model. Spain; 2Clinical Development, Porfolio & Methods: Data from two PK studies with rupatadine oral solution (1 mg/mL) were pooled: Strategy, Biorhom SL Grupo Uriach, Barcelona, Spain; 3Pharmacokinetic/ Study A, an extensive blood sampling study performed in 11 children (6–11 years old) who Pharmacodynamic Modeling and received a single oral dose of rupatadine; and Study B, a sparse blood sampling study in 40 Simulation. Institut de Recerca de children (2–5 years old) receiving multiple oral doses. A simultaneous population PK model l’Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain was developed using data available for all children. Using individual Bayesian estimates from the selected model, steady-state plasma concentrations for both studies were simulated and the non-parametric PK parameters were calculated for two age groups: 2–5 years (subgroup I) and 6–11 years (subgroup II). Results: A two-compartment model with first-order absorption and elimination with clear­ ance depending on body weight, better described the PK of rupatadine for 2–11 year old children. The plasma clearance dependence on weight was linear. The mean (SD) non- compartment PK parameters calculated using simulated plasma profiles at steady state were: Cmax, 2.54 (1.26) vs 1.96 (0.52) ng/mL; AUC0-24h, 10.74 (3.09) vs 10.38 (4.31) ng/mL/h; and t1/2, 12.28 (3.09) vs 15.94 (4.09) h, for children 6–11 and 2–5 years old, respectively. Conclusions: The PK of rupatadine depends on the weight of paediatric patients but not on their age. The dosage strategy adjusted by body weight in children 2–11 years old (2.5 mL if weight 10–25 kg, and 5 mL if ≥ 25 kg) provides similar exposure between the two groups of age, and to that obtained in adults with the 10 mg dose tablet formulation. Keywords: rupatadine, children, population pharmacokinetics Introduction Correspondence: Iñaki Izquierdo Manager of Clinical Development & Allergic rhinitis (AR) is an important and common condition that causes major Medical Advise; Porfolio & Strategy Area, morbidity in children and is a risk factor for the development of asthma. The Biorhom, S.L. (Grupo Uriach) Polígon Ind. Riera de Caldes, Avinguda Camí Reial, 51- successful treatment of AR in the pediatric population is essential to decrease the 57, Palau-solità i Plegamans, Barcelona, burden of this disease.1 Chronic spontaneous urticaria (CSU) is not frequent in 08184, Spain Email Inaki.izquierdo@uriach.com children, and it is defined as the appearance of wheals on a recurrent basis, over 6 Clinical Pharmacology: Advances and Applications 2021:13 115–122 115 © 2021 Santamaria et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Santamaria et al Dovepress weeks. Unfortunately, well designed randomized con­ The aim of the present work was to describe the PK of trolled trials (RCTs) for children are lacking as suggested rupatadine in paediatric patients overall, combining data in a recent review.2 Second generation H1 antihistamines from previous clinical trials (6–11 and 2–5 years) and to (SgH1) are effective and safe, and easy to administer in study whether the proposed doses are enough to assure children and adolescents. a similar exposure in paediatrics than in adults. Finally, Rupatadine is an inverse agonist H1 receptor and PAF new non-compartmental PK parameters for each age sub­ antagonist, approved by EMA, Health Canada, Japan and group are calculated and compared them with those in China regulatory agencies for the treatment of AR and adults. CSU for adults and adolescents at the dose 10 mg tablets.3 Furthermore, rupatadine oral solution was author­ Methods ized by the EMA, Health Canada and Israel agencies, Population more recently for children over 2 years at the same clinical We analysed data from two different clinical studies: indications.4–6 Study A11 was an open-label, single-centre study to The pharmacokinetics (PK) of many paediatric drugs, evaluate the PK of an oral solution (1 mg/mL) of rupata­ including the first and second generation antihistamines dine. Eleven paediatric patients aged 6 to 11 yr with used for the treatment of allergic diseases, has not been previous history of seasonal AR, who had to be sympto­ thoroughly investigated. Although dosage corrections matic with a baseline of 5 symptoms score: T5SS (nasal based on weight are commonly performed for children, it congestion, sneezing, rhinorrhea, itchy nose, mouth, throat should be borne in mind that a child is not a downscaled and/or ears and itchy, watery and red eyes score) ≥6 during model of an adult, and that human development is not each of the last 2 days before inclusion, were treated with a linear process. During growth, there are changes in the an oral solution of rupatadine (1mg/mL) adjusted by body composition of the body, as well as in the functional weight, over a period of 4 weeks in an open label design development of organs.7 PK data can support the drug study. development of paediatric formulations, and are particu­ Study B12 was a 28-day open-label, multicentre study larly useful to decide dose adjustments during the process. in which children 2–5 years old weighing ≥10 kg were To avoid frequent sampling in children, the US Food and included and administered the same oral solution. Forty- Drug Administration (FDA) and European Medicines four children were enrolled in this study, had to have Agency (EMA) recommend using a population pharmaco­ a history of mild-moderate AR, defined as either intermit­ kinetic (popPK) modelling and simulation approach during tent or persistent according to ARIA guideline.13 Children drug development.8,9 had to be symptomatic with a baseline of 5 symptoms In adults and adolescents, the model that best described score: T5SS (nasal congestion, sneezing, rhinorrhea, the PK data of rupatadine tablets was an open two- itchy nose, mouth, throat and/or ears and itchy, watery compartment model with first-order absorption and and red eyes score) ≥6 during each of the last 2 days elimination.10 before inclusion, and allergen skin prick test positive A single published study described the PK in children wheal of 3 mm greater than the diluent control, or between 6 and 11 years with an oral solution (1 mg/mL) of a positive (class 3 of positivity; ≥ 3.5–17.5 kU/L) on rupatadine specifically developed for this population.11 In ImmunoCAP® test. the study, clearance was found to be related to body weight Further details of inclusion and exclusion criteria are and PK parameters estimated for children within this age described in previous PK studies referred.11,12 range, were very similar to those reported for adults taking Both studies were approved by the corresponding Clinical 10 mg tablets, except for the volume of distribution. Research Ethics Committee and Health authorities and parent/ In a second PK study,12 in 2–5 year-old children, we guardians provided signed consent for children to participate optimised the estimation of the PK parameters by using in the study. Study A, conducted in Australia, was approved a popPK model with sparse sampling that minimised chil­ by the Ethics Committee of the Royal Children’s Hospital and dren’s discomfort during the study based on the hypothesis Murdoch Children’s Research Institute (Melbourne), and the that there are no differences in the PK of rupatadine Peninsula Private Hospital and Clinical Research Centre by age. (Rivercity, in addition to the Department of Health and 116 https://doi.org/10.2147/CPAA.S312911 Clinical Pharmacology: Advances and Applications 2021:13 DovePress Dovepress Santamaria et al Ageing, Therapeutic Goods Administration of the Australian at –4°C. Supernatant plasma was then separated in 2 aliquots government [Study number 2006/593]). Study B was of 1 mL each and frozen at –20°C until analysis. Plasma approved by the Ethics Committee for Clinical levels of rupatadine were measured using a validated liquid Pharmacology for Hungarian sites, the Pharma Ethics Ltd. chromatography–mass spectrometry (LC/MS) analytical Committee for South African sites and the pertinent Health method. The linear range of the assays was between 0.1 authorities. Both studies were performed in compliance with and 10 mg/L, 0.1 mg/L being the lower limit of quantifica­ the Declaration of Helsinki and were a part of the completed tion. The within- and between-run precision error was lower Paediatric Investigation Plan (EMEA-000582- PIP01-09). than 12.71%. Accuracy-related errors were within ±12.83% for this rupatadine-selective method. Study Design, Dosing and Blood Sampling Study A: Briefly, a complete concentration-time profile Population PK Model was obtained for each child after oral administration of One- and two-compartment disposition models with first- rupatadine 1 mg/mL solution. In this study, 2.5 mL of oral order absorption were fitted to the data with the first-order rupatadine solution (1 mg/mL) were administered to chil­ conditional estimation (FOCE) method using the NONMEM dren weighing between 10–25 kg, and 5 mL to those software (version 7.3)14 with a Fortran compiler (version 6). Models were parameterised in terms of volume of weighing ≥25 kg. A total of 8 blood samples were drawn distribution of central compartment (Vc/F); volume of at the following times: 30 min predose and 1, 2, 4, 8, 12 distribution of the peripheral compartment (Vp/F); total and 24 hours postdose (see Table 1). body clearance (CL/F); intercompartmental clearance Study B: Data included in this analysis were part of (CLd/F); first-order absorption rate constant (ka); and a larger study.12 The design and sampling were based on absorption lag time (Tlag). the optimal design obtained in our previous study.11 Interindividual variability was estimated assuming Children received 2.5 mL of oral rupatadine solution a proportional variance model, with exponential errors (1 mg/mL) once daily for 28 days when weighed <25 kg following a log-normal distribution, as given by the fol­ and 5 mL when ≥25 kg. Forty-four children were rando­ lowing equation: mized to one of the four sampling groups (approximately 10 children allocated to each group) described in Table 1. CLi ¼ CLpop � expðηiÞ where CLi is the true PK parameter of the i th individual, Analytical Assay of Rupatadine CLpop the population value for the typical individual, ηi is the In both studies, rupatadine concentrations in plasma were interpatient random effect with a mean of 0 and variance ω2 . determined as previously described.10 Blood samples (4 mL) To quantify the residual variability of the model addi­ were collected in lithium-heparin tubes at each time point. tive, proportional or combined (residual + proportional) The samples were then centrifuged at 3000 rpm for 10 min error models were evaluated. Although patients were Table 1 Study Design: Sampling Times Stage Rupatadine Dose Subjects Sampling Sampling Day (mL) (N) Time Group (h Post Dose) (day) Study A 2.5 mL (equivalent of 2.5 mg) with a body weight less than 25 kg; 11 Day 1 _ 0,50,1,2,4,8,12,24,48 and Day 28 – 24 5 mL (equivalent of 5 mg) with a body weight greater or equal than 25 kg. Study B 2.5 mL (equivalent of 2.5 mg) with a body weight less than 25 kg; 40 Day 14 1 (n=10) 0.25, 0.5, 2.25 and 2 (n=10) 4, 5.5, 6 5 mL (equivalent of 5 mg) with a body weight greater or equal than 3 (n=10) 6, 6.25, 7 25 kg. 4 (n=10) 8, 9, 10 Day 28 1,2,3,4 24 Clinical Pharmacology: Advances and Applications 2021:13 https://doi.org/10.2147/CPAA.S312911 117 DovePress Santamaria et al Dovepress recruited at different centres, the same analytical method proportion of individuals receiving each dose corre­ was applied to all samples since they were determined in sponded to that observed in the analysis dataset. Monte the same laboratory with identical procedures. We inves­ Carlo simulations were generated using fixed and random tigated whether the following covariates correlated with population estimates obtained from the final selected any of the above described parameters: age, gender, model. The mean profile and the intervals including 90% weight, height and body mass index (BMI). Age was of the simulated concentrations were plotted together with evaluated as continuous and categorical covariate accord­ the raw data. The agreement between simulations and ing to the following groups: group I (2–5 years) and group observations was assessed visually. II (6–11 years). As the number of available covariates was low, the evaluation of the potentially influential covariates was explored graphically first, and those showing PK Parameters Calculation We obtained complete plasma concentration profiles of a possible relationship with one or more parameters were rupatadine for 24 hours using individual Bayesian esti­ tested for significance in NONMEM, unless the covariates mated parameters. Sampling times were those used in the were correlated between them. In such a case, the covari­ study with children 6–11 years old (study A), so that we ate with the more possible clinical application was selected could compare the Area Under the Curve (AUC0-24) for further testing with NONMEM. A forward-inclusion and backwards-elimination approach was planned for between predicted and observed concentrations. The fol­ selecting the covariates of the model, although during the lowing PK parameters were calculated for each child after procedure we only used the forward-inclusion step. a single oral dose of rupatadine: maximum concentration Covariate inclusion was based on the precision of para­ (Cmax), time of maximum concentration (Tmax), the meter estimates, goodness-of-fit plots, and the minimum AUC0–24 calculated with the log-linear trapezoidal rule, value of the objective function (OF) provided by and the half-life (t1/2). These parameters were based on NONMEM. A covariate was introduced if it decreased simulated concentrations and calculated using a non- the OF by at least 3.84 points (P < 0.05). compartmental approach as implemented in the A model was considered superior to other nested mod­ WinNONLIN software (Professional Edition, Version 2.1, els on the basis of the following aspects: the OF value was Scientific Consulting, Pharsight, Mountain View, reduced by at least 3.84 points (P < 0.05, one degree of CA, USA). freedom; approximate χ2 distribution), an estimation error of the parameters was lower, goodness-of-fit of graphical Results representations, the convergence of the model, and the Data from 11 subjects (73 samples) from Study A were covariance matrix. analysed. In study B, 44 children were initially recruited, but data from 40 were analysed, because four children did Model Evaluation not have samples with concentrations above the limit of The final model was evaluated using Monte Carlo simula­ quantification. During the data analysis, one individual tions. A thousand individual concentration-time profiles of was excluded because data on the time of the last dose rupatadine were simulated after the administration of sin­ prior to blood extraction was missing. In summary, 120 gle daily doses of 2.5 mg or 5 mg for 28 days to test if the samples were available for this study and 193 plasma final model adequately described the observations. The concentrations of rupatadine were used for the data Table 2 Characteristics of the Patients Included in the Analysis Study Age Weight Height BMI Gender (Years) (kg) (m) (kg/m2) (Male/Female)* Study A 3.90 (1.0) 15.38 (3.14) 0.99 (0.08) 15.41 (1.89) 20/20 Study B 9.70 (1.4) 38.55 (14.31) 1.41 (0.28) 18.83 (3.95) 6/5 Note: Data are expressed as mean (standard deviation); *number. 118 https://doi.org/10.2147/CPAA.S312911 Clinical Pharmacology: Advances and Applications 2021:13 DovePress Dovepress Santamaria et al analysis. The demographics of the patients included in the Model Evaluation data analysis are summarized in Table 2. The prediction potential of the final selected model was evaluated using Monte Carlo simulations. The 90% pre­ Population Pharmacokinetic Model diction interval of the 1000 simulated profiles comprised The structural model that best fitted to the data was a two- most empirical observations from the whole dataset of, compartment model with elimination from the central com­ and slightly over predicted the interindividual variability in the final part of the graph (Figure 1). Therefore, we partment. The absorption phase was described by a first- considered that the model accurately predicted plasma order function associated with the Tlag. During model devel­ concentrations in paediatric patients. opment, data from one patient was excluded because the time of the last dose was missing, and the model did not reach Non-Compartmental PK Parameters convergence. Data showed high interindividual variability, Using individual Bayes estimates of the parameters, a full but only supported the estimation of interindividual variabil­ profile was simulated for each participant included in the ity in clearance (%) and central volume of distribution (%). data analysis. We obtained the parameters for each dosing The addition of interindividual variability in the absorption schedule: 2.5 mL or 5 mL of rupatadine oral solution phase decreased the OF value but increased the estimation (1 mg/mL) for children weighing 10 – ≤25 or 25 kg, errors and the shrinkage of the random parameters. Residual respectively. The median Tmax was 1 and 0.5 h, mean variability was explained using an additive error model. No Cmax (SD) was 1.96 (0.52) and 2.54 (1.26) ng/mL, differences between the study populations (Study A vs Study AUC0-24 was 10.38 (4.31) and 10.74 (3.09) ng/mL/h, and B) were found for any of the fixed parameters. An allometric mean t1/2 was 15.94 (4.09) and 12.28 (3.09) h for children scaling model was tested; however, the fit was better when 2–5 and 6–11 years old, respectively. weight was included using a linear function. This last model decreased 15 points the OF value and reduced the estimation Discussion error in all the parameters except for the Tlag. None of the Data from Studies A and B resulted in a complete PK other available covariates (age, gender, height and BMI) study of rupatadine in a paediatric population by using showed a statistical correlation with the parameters. Table 3 a popPK approach. This allowed us to propose dose lists the population estimates of the final selected model. recommendations for children between 2 and 11 years, considering a combination of two different experimental conditions (sparse and full blood sampling). Table 3 Population Parameter Estimates from the Final Model In Study A, 11 children 6–11 years were enrolled and Parameter Interindividual a limited population PK model was developed that enabled Estimate (RSE) Variability (RSE) the optimisation of the design in a subsequent PK study Ka (h−1) 0.498 (12.0) NE (Study B) in younger children, including a sparse sampling strategy as recommended by several authors.15 Therefore, Tlag (h) 0.15 (6.6) NE in the popPK model presented in this work we have CL/F(L/h)=θ1 θ1=120 (41.2) 38.9 (25.6) included overall data from 51 patients aged between 2 +θ2*/weight/20 θ2=198 (18.9) and 11 years. The developed model was structurally iden­ Vc/F (L) 118 (40.0) 139.6(39) tical to that previously described for older children.11 CLd/F (L/h) 210 (23.1) NE This article supports the finding that the PK of rupata­ dine does not depend on age, at least from 2 years old to Vp/F (L) 3730 (46.9) NE adults.10,11 The PK of rupatadine followed a two- Residual error (ng/ 0.16 (15.1) compartment model, as previously observed in older mL) children.11 The inclusion of 40 new children in the current Note: Interpatient variability was expressed as coefficient of variation. analysis reinforces the consistency of our results. The only Abbreviations: Ka, first-order absorption rate constant; CL/F, total body clear­ ance; Vc/F, apparent volume of distribution of the central compartment; CLd/F, covariate that influenced the PK of rupatadine was body apparent intercompartmental clearance; Vp/F, apparent volume of distribution of weight. When weight was considered in the model, our the peripheral compartment; Tlag, absorption lag time; RSE, residual standard error; NE, not estimated simulations predicted a comparable exposure in children Clinical Pharmacology: Advances and Applications 2021:13 https://doi.org/10.2147/CPAA.S312911 119 DovePress Santamaria et al Dovepress Figure 1 Visual predictive check of the final selected model. Data points represent the time profile of the observed plasma concentrations of rupatadine in children 2–11 years old after the administration of 2.5 mg or 5 mg doses. The solid grey area represents the 90% prediction interval of the simulated plasma concentrations over time, and the black line represents the mean of the simulated profiles. 2–5 and 6–11 years old or in adolescents and adults.8,10 (modelled as a linear relationship between clearance Paediatric PK studies usually cover a broader range of and weight) allowed us to recommend two different weights and heights than those performed in adults. As doses for children older than 2 years depending on the physiological hepatic elimination of drugs depends on their weight (< 25 kg or ≥25 kg). body size, weight, BMI or body area are expected covari­ The mean parameters estimated by a non- ates in the kinetic model in paediatrics.16 This result con­ compartmental analysis showed no differences in firms the adequacy of adjusting the dosage of rupatadine AUC0-24, Cmax or tmax at steady-state in paediatric subjects by weight, as observed with other antihistamines. between 2 and 11 years of age based on the simulated The effect of body weight on the PK of drugs in results. With respect to adults, rupatadine elimination half- paediatric patients has been assessed using either life (t1/2) seemed slightly longer in children than in allometric17 or empirical models.18 Although both pre­ adults;19 however, this difference does not likely have sent advantages, the main strength of empirical size a clinical impact on the response (efficacy or safety) to adjustments for PK parameters using body weight rupatadine and is probably due to the calculation of the t1/2 (especially if they have a simple structure), is their in adults based on shorter sampling observations and not easy translation into body weight based dosage recom­ on predictions up to 24 hours. In fact, safety and efficacy mendations that are more familiar to clinicians, such as results for both groups of age (2–5 and 6–11 years old) milligrams per kilogram of body weight.16 In our case, with the proposed dosing schedule were similar to those in the incorporation of body weight in the model the adult population.3 120 https://doi.org/10.2147/CPAA.S312911 Clinical Pharmacology: Advances and Applications 2021:13 DovePress Dovepress Santamaria et al A deeper analysis of the estimated parameters revealed attain similar plasma concentrations than in adults and that the volume of distribution was half for a child than for adolescents, thereby obtaining a similar pattern of efficacy an adult.20 However, when the volume of distribution is and safety margins. normalised by weight (kg), we found no differences between adults and children; and similar results have Acknowledgments been previously reported for desloratadine, epinastine or We would like to thank Dr. Noel Cranswick and Prof Paul levocetirizine.21–23 Potter, who were involved as clinical investigator and coor­ Drug clearance by CYP3A4, the enzyme that metabo­ dinator in Studies A and B, respectively. We would also like lizes rupatadine, is considered age-dependent. It is not to thank all the patients who participated in the studies and surprising that clearance did not depend on age in our the staff of the hospitals where the patients were treated. study, since a recent evaluation of the ontogeny function of CYP3A4 found that the maturation takes places before Author Contributions 2 years of age.24 Finally, since the active metabolites of All authors made substantial contributions to conception rupatadine, desloratadine and its hydroxylated dihydroxy- and design, acquisition of data, or analysis and interpreta­ desloratadine hydrochloride, maintain a similar exposure tion of data; took part in drafting the article or revising it ratio in children and adults (data on file Uriach), the critically for important intellectual content; agreed to sub­ concentrations of these metabolites were not included mit to the current journal; gave final approval of the (although determined) in the development of the model version to be published; and agree to be accountable for for the sake of simplicity. all aspects of the work. As limitation of study, we could not estimate the interindividual variability of Ka, nor that of lag time, Funding although data showed high interindividual variability in Marta Valle was supported by a grant (FIS CP04/00121) the absorption phase. As parameter estimation is highly from the Spanish Health Ministry in collaboration with dependent on sampling times, it is likely that the previous Institut de Recerca de l’Hospital de la Santa Creu i Sant model developed with only 11 children did not have Pau, Barcelona; she is a member of CIBERSAM (funded by sufficient information to estimate the interindividual the Spanish Health Ministry, Instituto de Salud Carlos III). variability associated with the absorption phase. However, this cannot yet be clarified due to the lack of Disclosure PK studies other than the one published by Peña et al in ES and II were full-time employees at Grupo Uriach at the 2008, using an adult population.10 Nonetheless, the time the clinical trials were performed. ES is currently absorption rate constant in children was similar to that affiliated with Novella Clinical Ltd and Marta Valle is reported for adults, despite the fact that adults received currently the scientific director of Clinical Pharmacology, tablets and children oral solution. With our model, we Modeling and Simulation of Parexel International SL. The have demonstrated that the optimal design of sampling authors report no other conflicts of interest in this work. can be effective in obtaining sufficient information for studying the PK of a drug without compromising the well- References being of children. 1. Barr JG, Al-Reefy H, Fox AT, Hopkins C. Allergic rhinitis in children. 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