Regular Article

Pharmacokinetics of the H2 Blocker Roxatidine Acetate Hydrochloridein Pediatric Patients, in Comparison with Healthy Adult Volunteers

Hidefumi NAKAMURA1, Hisashi KAWASHIMA2, Rieko AZUMA3,*,Ikuya SATO3, Koji NAGAO3 and Katsuhiko MIYAZAWA3

1National Center for Child Health and Development, Tokyo, Japan2Tokyo Medical University, Tokyo, Japan

3Clinical Development Center, ASKA Pharmaceutical Co., Ltd., Tokyo, Japan

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: Clinical studies were conducted to investigate the pharmacokinetics of roxatidine acetatehydrochloride capsules (ALTATμ CAPSULES) in children. In a single-dose pharmacokinetic (PK) study inpediatric patients aged between 6 and 14 years with acid-related diseases, 37.5mg or 75mg roxatidinecapsules were given orally, and blood samples were collected to determine the plasma roxatidineconcentrations. Meanwhile, a single-dose PK study in healthy adult volunteers was newly conducted;subjects were given 37.5mg, 75mg or 150mg roxatidine capsules. Differences were present between thePK parameters in pediatric patients and those in healthy adult volunteers. However, the CL/F and Vd/Fadjusted by body surface area (BSA) or body weight (BW) were comparable. A close correlation of the Cmax

and AUC0­¨ to the dose per unit BSA (mg/m2) or BW (mg/kg) was also shown. In the multiple-dose study inpediatric patients, no roxatidine accumulation in plasma was observed, as was the case with a previous studyin adults. These data show that the PK profile of roxatidine in pediatric patients is similar to the profile inhealthy adult volunteers when adjusted by BSA or BW.

Keywords: roxatidine; pediatric patients; single-dose; multiple-dose; pharmacokinetics

Introduction

A sustained release capsule formulation of the histamineH2 receptor antagonist roxatidine acetate hydrochloride¤ALTAT¬ CAPSULES, ASKA Pharmaceutical, Tokyo,Japan: hereinafter called roxatidine capsules¥ potently andcontinuously suppresses gastric acid secretion by competi-tively inhibiting the histamine H2 receptors located in gastricparietal cells,1,2¥ like other H2 receptor antagonists. Large-scale trials have shown that roxatidine acetate is as effec-tive as standard doses of cimetidine and ranitidine in thetreatment of patients with duodenal or gastric ulcer, andthe prevention of peptic ulcer recurrence.3¥ Previous studiesin adults showed at least 95% of the roxatidine acetatehydrochloride is absorbed into the blood after oral admin-istration,4¥ and the serum protein binding ratio is 9%.5¥ Theroxatidine does not inhibit the human cytochrome P450in vitro.6¥ The drug is mainly excreted into the urine and atleast 70% of the amount administered is excreted within

24 h.7¥ The elimination from the plasma is dependent onrenal function ¤creatinine clearance¥.8¥

Oral administration of 75mg of roxatidine twice daily hasbeen approved in adults for the treatment of acid-relateddiseases, such as gastric ulcers, duodenal ulcers, and refluxesophagitis. The drug has been used to treat acid-relateddiseases with excellent efficacy and safety since beingintroduced over 20 years ago.There has been extensive experience of roxatidine use

in adults, and information regarding safety, efficacy andpharmacokinetics has been accumulated. On the other hand,there has been minimal accumulation of data for dosage,safety or efficacy although H2 receptor antagonists in chil-dren have been commonly prescribed off-label in Japan. Tothe best of our knowledge, there has been no publicationspecifically addressing the pharmacokinetics of roxatidine inpediatric patients.In this article, the pharmacokinetics of roxatidine in

pediatric patients of age 6 to 14 years with acid-related

Received September 16, 2011; Accepted January 17, 2012J-STAGE Advance Published Date: January 31, 2012, doi:10.2133/dmpk.DMPK-11-RG-112*To whom correspondence should be addressed: Rieko AZUMA, Clinical Development Center, ASKA Pharmaceutical Co., Ltd., 2-5-1 Shibaura,Minato-ku, Tokyo 108-8532, Japan. Tel. +81-3-5484-8333, Fax. +81-3-5484-8356, E-mail: azuma-r@aska-pharma.co.jp

Drug Metab. Pharmacokinet. 27 (4): 422­429 (2012). Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

422

diseases is described and compared with that of healthyadult volunteers.

Methods

Clinical study: Three pharmacokinetic ¤PK¥ studies,one single-dose study in pediatric patients, one in healthyadult volunteers, and a multiple-dose study in pediatricpatients, were conducted. All studies were reviewed andapproved by the Institutional Review Board of each clinicaltrial site.Single-dose PK study in pediatric patientsThis study was a multi-center, open-label, dose-escalating

trial. Admitted pediatric patients aged between 5 and 14years, diagnosed with or suspected of having a gastriculcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellisonsyndrome, reflux esophagitis, acute gastritis, or a gastricmucosal lesion of chronic gastritis with an acute exacerbation¤erosion, bleeding, redness, and edema¥, were included;patients with serum creatinine exceeding the upper limitof normal range for age at each clinical study site wereexcluded. Some of the study sites used the publishedreference ranges of laboratory data in children.9¥

A total of 25 pediatric patients were enrolled in thisstudy after obtaining informed assent from the patientswhen applicable and informed consent from their parentsor legally acceptable representatives. The pediatric patientswere divided into four groups based on their age ¤5®9 or10®14 years¥ and the dosage ¤37.5 or 75mg¥. Roxatidinecapsules were given as follows: 37.5mg for age 5®9 years¤6 patients¥, 37.5mg for age 10®14 years ¤6 patients¥, 75mgfor age 5®9 years ¤6 patients¥, and 75mg for age 10®14years ¤7 patients¥. The patients were given the roxatidinecapsule orally with water in the morning after breakfast.Blood samples of 1mL each were collected at 0, 1, 2, 3, 4,6, 10, and 24 h after administration to determine the plasmaroxatidine concentrations.This study was conducted at National Center for Child

Health and Development ¤Tokyo¥, Tokyo MetropolitanKiyose Childrenös Hospital ¤Tokyo Metropolitan ChildrenösMedical Center, presently, Tokyo¥, Kanagawa ChildrenösMedical Center ¤Kanagawa¥, Osaka Medical Center andResearch Institute for Maternal and Child Health ¤Osaka¥,Tokyo Medical University Hospital ¤Tokyo¥, and Sapporo-Kosei General Hospital ¤Hokkaido¥ in Japan.Single-dose PK study in healthy adult volunteersThis study was a randomized, open-label, parallel-group

trial. The subjects were in good health based on medicalhistory, physical examination, and clinical laboratory exami-nations. Twenty-four healthy male subjects were enrolled inthis study after their informed consent was obtained.The subjects were divided into three groups and given

a roxatidine capsule of 37.5mg ¤8 subjects¥, 75mg ¤8subjects¥, or 150mg ¤8 subjects¥ orally with water in themorning after a fast of more than 10 h. Blood samples of2mL each were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,

and 24 h after administration to determine the plasmaroxatidine concentrations. This study was conducted atMaruyama Hospital ¤Shizuoka, Japan¥.Multiple-dose PK evaluation in pediatric patientsThis multiple-dose PK evaluation was conducted as a part

of a phase 3, multi-center, open-label trial. Pediatric patientsdiagnosed with or suspected of having gastric ulcer, duo-denal ulcer, or reflux esophagitis and requiring treatmentwere included; patients with serum creatinine exceeding theupper limit of normal range for age at each clinical study sitewere excluded.A total of 21 patients 6®14 years of age were enrolled

in this study after obtaining informed assent from thepatients and informed consent from their parents or legallyacceptable representatives. The patients were divided intotwo groups on the basis of their body weight ¤BW¥: a37.5mg roxatidine capsule was given orally to pediatricpatients weighing less than 30 kg ¤6 patients¥, and 75mgwas given to pediatric patients weighing 30 kg or more¤15 patients¥ with water twice a day for 8 weeks.Blood samples of 1mL each were collected in the

4th week and 8th week of administration to determinethe trough plasma roxatidine concentrations ¤Ctrough¥. Thisstudy was conducted at Sapporo-Kosei General Hospital¤Hokkaido¥, Tokyo Medical University Hospital ¤Tokyo¥,National Center for Child Health and Development¤Tokyo¥, Tokyo Metropolitan Childrenös Medical Center¤Tokyo¥, Saiseikai Yokohamashi Tobu Hospital ¤Kanagawa¥,Kanagawa Childrenös Medical Center ¤Kanagawa¥, OsakaGeneral Medical Center ¤Osaka¥ and Osaka Medical Centerand the Research Institute for Maternal and Child Health¤Osaka¥ in Japan.Roxatidine assays: The roxatidine acetate hydrochlo-

ride is rapidly converted to its active metabolite, roxatidine,by esterase in the plasma, liver, and small intestine.10¥

Therefore, the roxatidine concentration in plasma sampleswas determined using a LC/MS/MS method. The LC/MS/MS method was validated for selectivity, accuracy, pre-cision, recovery and stability in accordance with FDA guid-ance11¥ for bioanalytical method validation.To a plasma sample aliquot ¤50 µL¥, 1,000 µL of distilled

water, 100 µL of methanol, and 100 µL of internal standard¤roxatidine-d10¥ working solution were added. The solutionwas mixed and loaded on to the C8 solid-phase extractioncolumn, which was conditioned with 3mL of acetonitrileand 3mL of methanol, followed by 3mL of distilled water.The column was washed with 3mL of distilled water and2mL of acetonitrile. The extracted roxatidine and internalstandard were eluted with 2mL of methanol/triethylamine¤200:1, v/v¥. The eluate was evaporated to dryness undera stream of nitrogen gas on an aluminum block heater at40ôC. The residue was dissolved in 1mL of 0.05mol/Lammonium acetate/methanol ¤9:1, v/v¥ and injected intothe LC/MS/MS.The processed sample was analyzed using a Waters

Pharmacokinetics of Roxatidine Capsule in Pediatric Patients 423

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

ACQUITY UPLC¬ system ¤Waters Corp., Milford, MA¥coupled to an AB/MDS Sciex API5000 triple quadrupolemass spectrometer ¤AB Sciex, Foster City, CA¥. Chroma-tography was performed using a Shiseido CAPCELLPAKC18 MGII, 2.0mm I.D. ' 35mm, 5-µm column ¤Shiseido,Tokyo, Japan¥. Mobile phase A was 0.05mol/L ammoniumacetate/acetic acid ¤1,000:1, v/v¥, and mobile phase B wasmethanol/acetic acid ¤1,000:1, v/v¥. Roxatidine and theinternal standard were separated from endogenous matrixcomponents using a gradient elution. The initial mobilephase condition ¤70/30, A/B¥ was held for 0.5min, follow-ed by a linear gradient from 70/30 ¤A/B¥ to 5/95 ¤A/B¥over 2.5min. The mobile phase composition was thenreturned to the initial condition for an additional 1min. Theflow rate was 0.2mL/min, and the column temperaturewas 40ôC.The sample was ionized using a Turboionspray probe in the

positive-ion mode. The mass spectrometer was tuned for unitmass resolution, and data were collected using the multiplereaction monitoring ¤MRM¥ mode. The mass transitionsused to detect roxatidine and the internal standard werem/z 307 G m/z 114 and m/z 317G m/z 114, respec-tively, with a dwell time of 500ms for each transition.The calibration range was 1.00 ng/mL to 1,000 ng/mL, withthe lower limit of quantitation being 1.00 ng/mL.Pharmacokinetic analysis: The PK parameters were

estimated by non-compartment methods with WinNonlinProfessional Ver. 5.2.1 Software ¤Pharsight Corp., MountainView, CA¥.Maximum plasma concentration ¤Cmax¥, time of maximum

plasma concentration ¤Tmax¥, and trough plasma concen-tration ¤Ctrough¥ were obtained from the observed data.Elimination half-life ¤T1/2¥ was obtained as ln 2/Ðz, whereÐz was calculated by least squares linear regression of theterminal portion of the log-transformed plasma concen-tration-time curve. The area under the plasma concentrationvs. time curve from 0 to the last quantifiable concentration¤AUC0®t¥ was estimated using the linear trapezoidal rule.The AUC from 0 to infinity ¤AUC0®W¥ was obtainedas the sum of the ¤AUC0®t¥ and Clast/Ðz, where Clast is thelast measurable drug concentration. Apparent Total BodyClearance ¤CL/F¥ was calculated by DOSE/AUC0®W, andVolume of Distribution ¤Vd/F¥ was calculated by ¤CL/F¥/Ðz.Correlation coefficients were calculated using SAS 9.1.3¤SAS Institute Inc., Cary, NC¥. The PK parameters adjustedby body surface area ¤BSA¥ were obtained from ¤PKparameters¥/BSA, where BSA was calculated from theDuBois formulas.12¥ The PK parameters adjusted by BWwere obtained from ¤PK parameters¥/BW. The differencesbetween groups were tested by Studentös t test or analysis ofcovariance using SAS 9.1.3.Simulation of multiple-dose: The multiple-dose

data in pediatric patients were simulated with the super-position method using the mean plasma concentrations ofroxatidine from a single-dose PK study in pediatric patients

weighing less than 30 kg who took a 37.5mg roxatidinecapsule ¤n © 4¥ or weighing 30 kg or more who took 75mg¤n © 6¥.

Results

Analytical validation: The analysis of roxatidine andI.S. was highly selective with no interfering compounds. Thecalibration curve was linear over a concentration range of1.00®1,000 ng/mL and the correlation coefficient ¤r¥ wash0.999. Precision and accuracy for this method wereevaluated by calculating the intra- and inter-batch variationsof QC samples in five replicates at four concentrations¤1.00, 2.00, 40.0 and 800 ng/mL¥ for roxatidine. The intra-and inter-day precision ¤CV%¥ were less than 6.8% forroxatidine. The intra- and inter-day accuracy was within95.5% to 104.5% for roxatidine. The recovery of thesample preparation by solid-phase extraction on a C8column from plasma was estimated at three concentrationlevels of roxatidine. The extraction recoveries were 92.9,88.4 and 92.5% at levels of 2.00, 40.0 and 800 ng/mL,respectively. In freeze and thaw stability ¤%20ôC to roomtemperature¥, short-term stability at room temperatureand post-preparative stability ¤in an autosampler set at10ôC¥, roxatidine was stable for three cycles, 24 h and 76 h,respectively. Roxatidine in human plasma was stable for 185days storage at %20ôC or %80ôC. These validation resultssatisfied the criteria.Demographics: A list of the demographics of the

subjects in the single-dose PK study in pediatric patients,the single-dose PK study in healthy adult volunteers, andthe multiple-dose PK evaluation in pediatric patients wasprovided in Table 1. None of the demographic character-istics was abnormal. Serum creatinine of pediatric patientsand healthy adult volunteers were within normal range forage at each clinical study site.Differences in age, BW, and BSA were present between

the dosage groups in the multiple-dose PK evaluation inpediatric patients as the dosage was determined according toBW. The patients in the 37.5-mg group of the multiple-dosePK evaluation in pediatric patients were younger and had alower BW and BSA than those in other pediatric dosagegroups.Single-dose PK study in pediatric patients and

healthy adult volunteers: The plasma concentration-time curves for pediatric patients aged 6 to 14 years andhealthy adult volunteers are shown in Figure 1. The profilesof the plasma roxatidine concentrations in the pediatricpatients were similar to those in the healthy adult volunteers.Pharmacokinetic parameters of roxatidine in the pediatricpatients and healthy adult volunteers are shown in Table 2.In the pediatric patients, Cmax, AUC0®t, and AUC0®W

increased proportionally for dose. Tmax and T1/2 weregenerally constant, CL/F and Vd/F were similar across thedosing groups. Cmax, AUC0®t, and AUC0®W in the healthyadult volunteers increased linearly with the dose.

Hidefumi NAKAMURA, et al.424

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

When the PK parameters of roxatidine in the pediatricpatients and healthy adult volunteers were compared, themean Cmax and AUC0®W in the pediatric patients following37.5 and 75mg was significantly higher than those in healthyadult volunteers ªCmax: approx. 2.2-fold ¤p g 0.001¥ and1.6-fold ¤p g 0.01¥, respectively, AUC0®W: approx. 1.5-fold¤p g 0.01¥ at each dose«.Meanwhile, CL/F and Vd/F in the pediatric patients

following 37.5 and 75mg was significantly lower than

those in healthy adult volunteers ªCL/F: approx. 0.69-fold¤p g 0.01¥ and 0.70-fold ¤p g 0.01¥, respectively, Vd/F:approx. 0.59-fold ¤p g 0.001¥ and 0.59-fold ¤p g 0.01¥,respectively¥«.An investigation of the relationships of CL/F and Vd/F

to BSA or BW revealed a close correlation ¤Fig. 2¥. Whenadjusted by BSA or BW, the CL/F and Vd/F in the pediatricpatients and healthy adult volunteers were comparable¤Table 3¥. Both Cmax and AUC0-W in the pediatric patientsand healthy adult volunteers were closely correlated withthe dose per unit BSA ¤mg/m2¥ ¤Cmax: r © 0.8406, AUC0®W:r © 0.9329¥ and also closely correlated with the dose perunit BW ¤mg/kg¥ ¤Cmax: r © 0.8257, AUC0®W: r © 0.8455,Fig. 3¥.Multiple-dose PK evaluation in pediatric pa-

tients: Steady state plasma trough roxatidine concen-trations ¤Ctrough¥ at the 2nd, 4th, and 8th week of repeated

Table 1. Demographics of each study

37.5mg 75mg 150mg

Single-dose PK study in pediatric patientsN 12 13Sex male 8 9

female 4 4Age ¤years¥ 9.8 + 2.1 10.3 + 2.7

¤range¥ ¤7®14¥ ¤6®14¥Weight ¤kg¥ 34.68 + 9.34 33.70 + 11.51BSA ¤m2¥ 1.128 + 0.157 1.135 + 0.248Serum creatinine ¤mg/dL¥ 0.410 + 0.118 0.417 + 0.121

Single-dose PK study in healthy adult volunteersN 8 8 8Sex male 8 8 8Age ¤years¥ 30.3 + 7.3 37.5 + 7.0 33.4 + 7.0Weight ¤kg¥ 63.46 + 5.51 65.14 + 8.47 63.73 + 8.36BSA ¤m2¥ 1.755 + 0.066 1.769 + 0.133 1.765 + 0.133Serum creatinine ¤mg/dL¥ 0.794 + 0.060 0.781 + 0.141 0.824 + 0.102

Multiple-dose PK evaluation in pediatric patientsN 6 15Sex male 3 8

female 3 7Age ¤years¥ 8.2 + 2.0 10.8 + 2.0

¤range¥ ¤6®12¥ ¤7®14¥Weight ¤kg¥ 23.33 + 3.44 38.63 + 5.64BSA ¤m2¥ 0.877 + 0.060 1.242 + 0.111Serum creatinine ¤mg/dL¥ 0.367 + 0.071 0.424 + 0.088

Mean + S.D.

Fig. 1. Plasma roxatidine concentration (mean + S.D.) in pediatric patients and healthy adult volunteers(a) Profiles after administration of roxatidine capsule (37.5, 75mg) to pediatric patients. (b) Profiles after administration of roxatidine capsule(37.5, 75, 150mg) to healthy adult volunteers.

Table 2. Pharmacokinetic parameters of roxatidine in pedia-tric patients and healthy adult volunteers

37.5mg 75mg 150mg

Pediatricpatients

Healthy adultvolunteers

Pediatricpatients

Healthy adultvolunteers

Healthy adultvolunteers

N 12 8 13 8 8Cmax

¤ng/mL¥354 + 131 158 + 20 530 + 148 329 + 54 629 + 67

Tmax ¤h¥a 2.0 2.5 3.0 3.0 2.02.0®6.0 1.5®3.0 1.0®6.0 2.0®3.0 2.0®3.0

AUC0®t

¤ng&h/mL¥1,995 + 622 1,273 + 228 3,513 + 878 2,310 + 382 5,046 + 624

AUC0®W

¤ng&h/mL¥2,054 + 619 1,353 + 249 3,587 + 890 2,424 + 397 5,275 + 696

T1/2 ¤h¥ 4.6 + 1.1 5.6 + 0.3 4.2 + 0.9 5.0 + 0.6 5.0 + 0.4CL/F

¤L/h¥19.6 + 5.1 28.6 + 5.3 22.4 + 6.9 31.8 + 6.0 28.8 + 3.5

Vd/F ¤L¥ 134 + 55 229 + 41 138 + 73 232 + 62 208 + 29

Mean + S.D.aUpper: median values, lower: range ¤min®max¥.

Pharmacokinetics of Roxatidine Capsule in Pediatric Patients 425

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

doses were almost constant in children ¤Table 4¥. Asimulation of roxatidine concentration profile after multipledoses was conducted using the superposition method withthe mean plasma roxatidine concentrations in the single-dosePK study in pediatric patients. The results of the simulationwere consistent with the measured Ctrough at the respectivetime ¤Fig. 4¥.

Discussion

The PK profile of roxatidine capsule in pediatric patientsaged between 6 and 14 years was characterized andcompared to that in healthy adult volunteers.

A number of assay methods have been developed for thedetermination of roxatidine in biological samples.13®15¥

However, blood sample volumes for pediatric studies shouldbe minimized, and reduction of sample volumes was neces-sary. Therefore we developed a highly sensitive assay forthe determination of roxatidine concentration. The necessaryplasma volumes for each determination was reduced to50 µL compared to 1mL in adult trials previously per-formed, and our analytical method provided the advantagesof high sensitivity with a limit of quantification ¤LOQ¥ of1 ng/mL. The obtained PK parameters this time in healthyadult volunteers were comparable with those reportedrecently.14,15¥

Cmax and AUC0®W in the pediatric patients following 37.5or 75mg were higher than those in the healthy adultvolunteers following the same doses, while Vd/F and CL/Fwere lower than those in the healthy adult volunteers. Aninvestigation of the relationships of Vd/F to BSA or BW

Fig. 2. The relationship between BSA or BW to CL/F and Vd/F in pediatric patients and healthy adult volunteersClosed circles, pediatric patients; open circles, healthy adult volunteers. (a) BSA and CL/F. Correlation coefficient ¦ 0.7882. (b) BWand CL/F. Correlation coefficient ¦ 0.7837. (c) BSA and Vd/F. Correlation coefficient ¦ 0.7583. (d) BW and Vd/F. Correlation coefficient ¦0.7363.

Table 3. CL/F and Vd/F adjusted by BSA or BW in pediatricpatients and healthy adult volunteers

37.5mg 75mg 150mg

p valueaPediatricpatients

Healthyadult

volunteers

Pediatricpatients

Healthyadult

volunteers

Healthyadult

volunteers

Pharmacokinetic parameters adjusted by BSAN 12 8 13 8 8CL/F¤L/h/m2¥

17.3 + 3.5 16.2 + 2.8 19.7 + 3.6 17.9 + 2.3 16.4 + 1.9 0.0703

Vd/F¤L/m2¥

117 + 40 130 + 22 119 + 39 130 + 28 118 + 19 0.6426

Pharmacokinetic parameters adjusted by BWN 12 8 13 8 8CL/F¤L/h/kg¥

0.58 + 0.13 0.45 + 0.08 0.68 + 0.14 0.49 + 0.05 0.46 + 0.07 0.5985

Vd/F¤L/kg¥

3.90 + 1.31 3.63 + 0.67 4.13 + 1.24 3.55 + 0.71 3.31 + 0.63 0.9392

Mean + S.D.aAnalysis of covariance.

Table 4. The mean trough roxatidine concentrations (Ctrough)in the multiple-dose PK evaluation in pediatric patients

37.5mg 75mg

N 6 15

2nd week26.8

¯¤n © 1¥

4th week24.9 + 8.9 65.4 + 43.9¤n © 5¥ ¤n © 14¥

8th week24.8 + 19.5 61.7 + 49.1

¤n © 5¥ ¤n © 13¥

Mean + S.D. ¤ng/mL¥.

Hidefumi NAKAMURA, et al.426

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

revealed close correlation. Vd/F of roxatidine in the pedia-tric patients and healthy adult volunteers were comparablewhen adjusted by BSA or BW. Similarly, CL/F in thepediatric patients and healthy adult volunteers were com-parable when adjusted by BSA or BW. The differences inCmax and AUC0®W are therefore most likely attributable todifferences in body size between children and adults. Theabsorption and elimination processes of roxatidine capsule inpediatric patients do not appear to differ substantially from

the healthy adult volunteers, because Vd/F, CL/F adjustedby BSA or BW and also Tmax in the pediatric patients weresimilar to the adult values.The close correlation of the Cmax and AUC0®W to the

dose per unit BSA ¤mg/m2¥ in the pediatric patients andhealthy adult volunteers shows that the PK profile ofroxatidine capsule in pediatric patients is similar to theprofile in healthy adult volunteers. Similar results wereobtained for the dose per BW ¤mg/kg¥.

Fig. 3. The relationship between dose adjusted by BSA or BW to Cmax or AUC0–W in pediatric patients and healthy adult volunteersClosed circles, pediatric patients; open circles, healthy adult volunteers; solid line, regression line. (a) Dose adjusted by BSA (mg/m2) andCmax. Correlation coefficient ¦ 0.8406. (b) Dose adjusted by BW (mg/kg) and Cmax. Correlation coefficient ¦ 0.8257. (c) Dose adjusted by BSA(mg/m2) and AUC0–W. Correlation coefficient ¦ 0.9329. (d) Dose adjusted by BW (mg/kg) and AUC0–W. Correlation coefficient ¦ 0.8455.

Fig. 4. Profiles of plasma roxatidine concentrations after administration of roxatidine capsule to pediatric patients in the single-dosePK study and multiple-dose profiles simulated from single-dose PK study dataThe multiple-dose data in pediatric patients were simulated with the superposition method using the mean plasma concentrations of roxatidinefrom the single-dose PK study in pediatric patients weighing less than 30 kg who took a 37.5mg roxatidine capsule (n ¦ 4) or weighing 30 kg ormore who took 75mg (n ¦ 6). Ctrough in the multiple-dose PK evaluation in pediatric patients is shown. Solid line, 37.5mg roxatidine capsule;broken line, 75mg; open circles, Ctrough (mean + S.D.) 37.5mg at the second week (n ¦ 1), at the 4th week (n ¦ 5), and at the 8th week (n ¦ 5);closed circles, Ctrough (mean + S.D.) 75mg at the 4th week (n ¦ 14) and at the 8th week (n ¦ 13).

Pharmacokinetics of Roxatidine Capsule in Pediatric Patients 427

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Roxatidine excretion is dependent on renal function. T1/2

has been reported to be prolonged, and AUC was increasedin renal failure with low creatinine clearance. The dosageadjustment is necessary in renal failure.8¥ The pediatricpatients with renal dysfunction were excluded in our stud-ies, and influence of decreased renal function could notbe evaluated. As renal function ¤creatinine clearance¥ perBSA in children aged 2 years or older is reported to becomparable to that in adults,16¥ the PK profile of roxatidinecapsules in children aged 6 years or older is expected tobe similar to that in adults. This is consistent with the resultsof our PK studies in pediatric patients and healthy adultvolunteers.The results of a simulation of plasma roxatidine con-

centrations after multiple doses based on the data of thesingle-dose PK study in pediatric patients were consist-ent with the measured trough levels in the multiple-dose PKevaluation in pediatric patients. This means that the steadystate was reached, and that accumulation of roxatidine inplasma did not occur after multiple doses. Accumulationwith roxatidine multiple doses did not occur in adults,either.17¥

Gastric acid secretion reaches a level similar to that inadults by age 3 to 4 years.18¥ A pediatric pharmacodynamic¤PD¥ study with gastric pH as an endpoint was conducted ¤tobe published elsewhere¥, and the results were comparable tothat in other clinical studies of healthy adult volunteers.19,20¥

Therefore, PK and PD profile of roxatidine in pediatricpatients aged 6 years or older appears to be similar to thatin adults. Clinical efficacy was observed in a phase 3 studyas well.In conclusion, this investigation of the PK profile of

roxatidine capsules in pediatric patients revealed the PKprofile in children to be similar to that in adults when thedata were adjusted by BSA or BW. This investigation alsoshowed that the optimal roxatidine capsule dosage can becalculated according to the BSA or BW in patients aged 6years or older. As the roxatidine capsule has a broad safetymargin, the clinical dosage can be conveniently determinedbased on BW instead of BSA. Based on these data, thedosage of roxatidine approved by Pharmaceuticals andMedical Devices Agency for the pediatric patients with acid-related disease is 37.5mg for those weighing less than 30 kg,and 75mg for those weighing 30 kg or more.

Acknowledgments: The authors thank all investigatorsand investigatorsö cooperators in the following sites.Hamamatsu University School of Medicine: MitsuyoshiNakashima, Saiseikai Yokohamashi Tobu Hospital: AyanoInui, Miyagi Childrenös Hospital: Daiki Abukawa, MaruyamaHospital: Shogo Sesoko, Sapporo-Kosei General Hospital:Mutsuko Konno, National Center for Child Healthand Development: Katsuhiro Arai, Tokyo MetropolitanChildrenös Medical Center: Yuko Hamasaki, KanagawaChildrenös Medical Center: Masato Shinkai, Eihiko

Takahashi, Osaka General Medical Center: Hitoshi Tajiri,Osaka Medical Center and the Research Institute forMaternal and Child Health: Shinobu Ida.

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