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

Hidefumi NAKAMURA1,HisashiKAWASHIMA2,RiekoAZUMA3,*, Ikuya SATO3,KojiNAGAO3 and Katsuhiko MIYAZAWA3 1National Center for Child Health and Development, Tokyo, Japan 2Tokyo 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 acetate hydrochloride capsules (ALTATμ CAPSULES) in children. In a single-dose pharmacokinetic (PK) study in pediatric patients aged between 6 and 14 years with acid-related diseases, 37.5 mg or 75 mg roxatidine capsules were given orally, and blood samples were collected to determine the plasma roxatidine concentrations. Meanwhile, a single-dose PK study in healthy adult volunteers was newly conducted; subjects were given 37.5 mg, 75 mg or 150 mg roxatidine capsules. Differences were present between the PK parameters in pediatric patients and those in healthy adult volunteers. However, the CL/F and Vd/F

adjusted by body surface area (BSA) or body weight (BW) were comparable. A close correlation of the Cmax 2 and AUC0¨ to the dose per unit BSA (mg/m ) or BW (mg/kg) was also shown. In the multiple-dose study in pediatric patients, no roxatidine accumulation in plasma was observed, as was the case with a previous study in adults. These data show that the PK proﬁle of roxatidine in pediatric patients is similar to the proﬁle in healthy adult volunteers when adjusted by BSA or BW.

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

24 h.7¥ The elimination from the plasma is dependent on Introduction ¥ renal function ¤creatinine clearance¥.8 A sustained release capsule formulation of the histamine Oral administration of 75 mg of roxatidine twice daily has H2 receptor antagonist roxatidine acetate hydrochloride been approved in adults for the treatment of acid-related ¤ALTAT¬ CAPSULES, ASKA Pharmaceutical, Tokyo, diseases, such as gastric ulcers, duodenal ulcers, and reflux Japan: hereinafter called roxatidine capsules¥ potently and esophagitis. The drug has been used to treat acid-related continuously suppresses gastric acid secretion by competi- diseases with excellent efficacy and safety since being tively inhibiting the histamine H2 receptors located in gastric introduced over 20 years ago. 1,2¥ parietal cells, like other H2 receptor antagonists. Large- There has been extensive experience of roxatidine use scale trials have shown that roxatidine acetate is as effec- in adults, and information regarding safety, efficacy and tive as standard doses of cimetidine and ranitidine in the pharmacokinetics has been accumulated. On the other hand, treatment of patients with duodenal or gastric ulcer, and there has been minimal accumulation of data for dosage, 3¥ fi the prevention of peptic ulcer recurrence. Previous studies safety or ef cacy although H2 receptor antagonists in chil- in adults showed at least 95% of the roxatidine acetate dren have been commonly prescribed off-label in Japan. To hydrochloride is absorbed into the blood after oral admin- the best of our knowledge, there has been no publication istration,4¥ and the serum protein binding ratio is 9%.5¥ The specifically addressing the pharmacokinetics of roxatidine in roxatidine does not inhibit the human cytochrome P450 pediatric patients. in vitro.6¥ The drug is mainly excreted into the urine and at In this article, the pharmacokinetics of roxatidine in least 70% of the amount administered is excreted within pediatric patients of age 6 to 14 years with acid-related

Received September 16, 2011; Accepted January 17, 2012 J-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: [email protected]

422 Pharmacokinetics of Roxatidine Capsule in Pediatric Patients 423 diseases is described and compared with that of healthy and 24 h after administration to determine the plasma adult volunteers. roxatidine concentrations. This study was conducted at Maruyama Hospital ¤Shizuoka, Japan¥. Methods Multiple-dose PK evaluation in pediatric patients Clinical study: Three pharmacokinetic ¤PK¥ studies, This multiple-dose PK evaluation was conducted as a part one single-dose study in pediatric patients, one in healthy of a phase 3, multi-center, open-label trial. Pediatric patients adult volunteers, and a multiple-dose study in pediatric diagnosed with or suspected of having gastric ulcer, duo- patients, were conducted. All studies were reviewed and denal ulcer, or reﬂux esophagitis and requiring treatment approved by the Institutional Review Board of each clinical were included; patients with serum creatinine exceeding the trial site. upper limit of normal range for age at each clinical study site Single-dose PK study in pediatric patients were excluded. This study was a multi-center, open-label, dose-escalating A total of 21 patients 6®14 years of age were enrolled trial. Admitted pediatric patients aged between 5 and 14 in this study after obtaining informed assent from the years, diagnosed with or suspected of having a gastric patients and informed consent from their parents or legally ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison acceptable representatives. The patients were divided into syndrome, reﬂux esophagitis, acute gastritis, or a gastric two groups on the basis of their body weight ¤BW¥:a mucosal lesion of chronic gastritis with an acute exacerbation 37.5 mg roxatidine capsule was given orally to pediatric ¤erosion, bleeding, redness, and edema¥, were included; patients weighing less than 30 kg ¤6 patients¥, and 75 mg patients with serum creatinine exceeding the upper limit was given to pediatric patients weighing 30 kg or more of normal range for age at each clinical study site were ¤15 patients¥ with water twice a day for 8 weeks. excluded. Some of the study sites used the published Blood samples of 1 mL each were collected in the reference ranges of laboratory data in children.9¥ 4th week and 8th week of administration to determine ¤ ¥ A total of 25 pediatric patients were enrolled in this the trough plasma roxatidine concentrations Ctrough . This study after obtaining informed assent from the patients study was conducted at Sapporo-Kosei General Hospital when applicable and informed consent from their parents ¤Hokkaido¥, Tokyo Medical University Hospital ¤Tokyo¥, or legally acceptable representatives. The pediatric patients National Center for Child Health and Development were divided into four groups based on their age ¤5®9or ¤Tokyo¥, Tokyo Metropolitan Childrenös Medical Center 10®14 years¥ and the dosage ¤37.5 or 75 mg¥. Roxatidine ¤Tokyo¥, Saiseikai Yokohamashi Tobu Hospital ¤Kanagawa¥, capsules were given as follows: 37.5 mg for age 5®9 years Kanagawa Childrenös Medical Center ¤Kanagawa¥, Osaka ¤6 patients¥, 37.5 mg for age 10®14 years ¤6 patients¥,75mg General Medical Center ¤Osaka¥ and Osaka Medical Center for age 5®9 years ¤6 patients¥, and 75 mg for age 10®14 and the Research Institute for Maternal and Child Health years ¤7 patients¥. The patients were given the roxatidine ¤Osaka¥ in Japan. capsule orally with water in the morning after breakfast. Roxatidine assays: The roxatidine acetate hydrochlo- Blood samples of 1 mL each were collected at 0, 1, 2, 3, 4, ride is rapidly converted to its active metabolite, roxatidine, 6, 10, and 24 h after administration to determine the plasma by esterase in the plasma, liver, and small intestine.10¥ roxatidine concentrations. Therefore, the roxatidine concentration in plasma samples This study was conducted at National Center for Child was determined using a LC/MS/MS method. The LC/MS/ Health and Development ¤Tokyo¥, Tokyo Metropolitan MS method was validated for selectivity, accuracy, pre- Kiyose Childrenös Hospital ¤Tokyo Metropolitan Childrenös cision, recovery and stability in accordance with FDA guid- Medical Center, presently, Tokyo¥, Kanagawa Childrenös ance11¥ for bioanalytical method validation. Medical Center ¤Kanagawa¥, Osaka Medical Center and To a plasma sample aliquot ¤50 µL¥, 1,000 µL of distilled Research Institute for Maternal and Child Health ¤Osaka¥, water, 100 µL of methanol, and 100 µL of internal standard ¤ ¥ ¤ ¥ Tokyo Medical University Hospital Tokyo , and Sapporo- roxatidine-d10 working solution were added. The solution Kosei General Hospital ¤Hokkaido¥ in Japan. was mixed and loaded on to the C8 solid-phase extraction Single-dose PK study in healthy adult volunteers column, which was conditioned with 3 mL of acetonitrile This study was a randomized, open-label, parallel-group and 3 mL of methanol, followed by 3 mL of distilled water. trial. The subjects were in good health based on medical The column was washed with 3 mL of distilled water and history, physical examination, and clinical laboratory exami- 2 mL of acetonitrile. The extracted roxatidine and internal nations. Twenty-four healthy male subjects were enrolled in standard were eluted with 2 mL of methanol/triethylamine this study after their informed consent was obtained. ¤200:1, v/v¥. The eluate was evaporated to dryness under The subjects were divided into three groups and given a stream of nitrogen gas on an aluminum block heater at a roxatidine capsule of 37.5 mg ¤8 subjects¥,75mg¤8 40ôC. The residue was dissolved in 1 mL of 0.05 mol/L subjects¥, or 150 mg ¤8 subjects¥ orally with water in the ammonium acetate/methanol ¤9:1, v/v¥ and injected into morning after a fast of more than 10 h. Blood samples of the LC/MS/MS. 2 mL each were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, The processed sample was analyzed using a Waters

ACQUITY UPLC¬ system ¤Waters Corp., Milford, MA¥ weighing less than 30 kg who took a 37.5 mg roxatidine coupled to an AB/MDS Sciex API5000 triple quadrupole capsule ¤n © 4¥ or weighing 30 kg or more who took 75 mg mass spectrometer ¤AB Sciex, Foster City, CA¥. Chroma- ¤n © 6¥. tography was performed using a Shiseido CAPCELLPAK Results C18 MGII, 2.0 mm I.D. ' 35 mm, 5-µm column ¤Shiseido, Tokyo, Japan¥. Mobile phase A was 0.05 mol/L ammonium Analytical validation: The analysis of roxatidine and acetate/acetic acid ¤1,000:1, v/v¥, and mobile phase B was I.S. was highly selective with no interfering compounds. The methanol/acetic acid ¤1,000:1, v/v¥. Roxatidine and the calibration curve was linear over a concentration range of internal standard were separated from endogenous matrix 1.00®1,000 ng/mL and the correlation coefficient ¤r¥ was components using a gradient elution. The initial mobile h0.999. Precision and accuracy for this method were phase condition ¤70/30, A/B¥ was held for 0.5 min, follow- evaluated by calculating the intra- and inter-batch variations ed by a linear gradient from 70/30 ¤A/B¥ to 5/95 ¤A/B¥ of QC samples in five replicates at four concentrations over 2.5 min. The mobile phase composition was then ¤1.00, 2.00, 40.0 and 800 ng/mL¥ for roxatidine. The intra- returned to the initial condition for an additional 1 min. The and inter-day precision ¤CV%¥ were less than 6.8% for flow rate was 0.2 mL/min, and the column temperature roxatidine. The intra- and inter-day accuracy was within was 40ôC. 95.5% to 104.5% for roxatidine. The recovery of the The sample was ionized using a Turboionspray probe in the sample preparation by solid-phase extraction on a C8 positive-ion mode. The mass spectrometer was tuned for unit column from plasma was estimated at three concentration mass resolution, and data were collected using the multiple levels of roxatidine. The extraction recoveries were 92.9, reaction monitoring ¤MRM¥ mode. The mass transitions 88.4 and 92.5% at levels of 2.00, 40.0 and 800 ng/mL, used to detect roxatidine and the internal standard were respectively. In freeze and thaw stability ¤%20ôC to room m/z 307 G m/z 114 and m/z 317 G m/z 114, respec- temperature¥, short-term stability at room temperature tively, with a dwell time of 500 ms for each transition. and post-preparative stability ¤in an autosampler set at The calibration range was 1.00 ng/mL to 1,000 ng/mL, with 10ôC¥, roxatidine was stable for three cycles, 24 h and 76 h, the lower limit of quantitation being 1.00 ng/mL. respectively. Roxatidine in human plasma was stable for 185 Pharmacokinetic analysis: The PK parameters were days storage at %20ôCor%80ôC. These validation results estimated by non-compartment methods with WinNonlin satisfied the criteria. Professional Ver. 5.2.1 Software ¤Pharsight Corp., Mountain Demographics: A list of the demographics of the View, CA¥. subjects in the single-dose PK study in pediatric patients, ¤ ¥ Maximum plasma concentration Cmax , time of maximum the single-dose PK study in healthy adult volunteers, and ¤ ¥ plasma concentration Tmax , and trough plasma concen- the multiple-dose PK evaluation in pediatric patients was ¤ ¥ tration Ctrough were obtained from the observed data. provided in Table 1. None of the demographic character- ¤ ¥ Ð Elimination half-life T1/2 was obtained as ln 2/ z, where istics was abnormal. Serum creatinine of pediatric patients Ð z was calculated by least squares linear regression of the and healthy adult volunteers were within normal range for terminal portion of the log-transformed plasma concen- age at each clinical study site. tration-time curve. The area under the plasma concentration Differences in age, BW, and BSA were present between vs. time curve from 0 to the last quantifiable concentration the dosage groups in the multiple-dose PK evaluation in ¤ ¥ AUC0®t was estimated using the linear trapezoidal rule. pediatric patients as the dosage was determined according to fi ¤ ¥ The AUC from 0 to in nity AUC0®W was obtained BW. The patients in the 37.5-mg group of the multiple-dose ¤ ¥ Ð as the sum of the AUC0®t and Clast/ z, where Clast is the PK evaluation in pediatric patients were younger and had a last measurable drug concentration. Apparent Total Body lower BW and BSA than those in other pediatric dosage ¤ ¥ Clearance CL/F was calculated by DOSE/AUC0®W, and groups. ¤ ¥ ¤ ¥ Ð Volume of Distribution Vd/F was calculated by CL/F / z. Single-dose PK study in pediatric patients and Correlation coefficients were calculated using SAS 9.1.3 healthy adult volunteers: The plasma concentration- ¤SAS Institute Inc., Cary, NC¥. The PK parameters adjusted time curves for pediatric patients aged 6 to 14 years and by body surface area ¤BSA¥ were obtained from ¤PK healthy adult volunteers are shown in Figure 1. The profiles parameters¥/BSA, where BSA was calculated from the of the plasma roxatidine concentrations in the pediatric DuBois formulas.12¥ The PK parameters adjusted by BW patients were similar to those in the healthy adult volunteers. were obtained from ¤PK parameters¥/BW. The differences Pharmacokinetic parameters of roxatidine in the pediatric between groups were tested by Studentös t test or analysis of patients and healthy adult volunteers are shown in Table 2. covariance using SAS 9.1.3. In the pediatric patients, Cmax, AUC0®t, and AUC0®W Simulation of multiple-dose: The multiple-dose increased proportionally for dose. Tmax and T1/2 were data in pediatric patients were simulated with the super- generally constant, CL/F and Vd/F were similar across the position method using the mean plasma concentrations of dosing groups. Cmax, AUC0®t, and AUC0®W in the healthy roxatidine from a single-dose PK study in pediatric patients adult volunteers increased linearly with the dose.

When the PK parameters of roxatidine in the pediatric those in healthy adult volunteers ªCL/F: approx. 0.69-fold patients and healthy adult volunteers were compared, the ¤p g 0.01¥ and 0.70-fold ¤p g 0.01¥, respectively, Vd/F: ¤ g ¥ ¤ g ¥ mean Cmax and AUC0®W in the pediatric patients following approx. 0.59-fold p 0.001 and 0.59-fold p 0.01 , 37.5 and 75 mg was signiﬁcantly higher than those in healthy respectively¥«. ª ¤ g ¥ adult volunteers Cmax: approx. 2.2-fold p 0.001 and An investigation of the relationships of CL/F and Vd/F ¤ g ¥ ¤ ¥ 1.6-fold p 0.01 , respectively, AUC0®W: approx. 1.5-fold to BSA or BW revealed a close correlation Fig. 2 . When ¤p g 0.01¥ at each dose«. adjusted by BSA or BW, the CL/F and Vd/F in the pediatric Meanwhile, CL/F and Vd/F in the pediatric patients patients and healthy adult volunteers were comparable ﬁ ¤ ¥ following 37.5 and 75 mg was signi cantly lower than Table 3 . Both Cmax and AUC0-W in the pediatric patients and healthy adult volunteers were closely correlated with ¤ 2¥¤ © ®W Table 1. Demographics of each study the dose per unit BSA mg/m Cmax:r 0.8406, AUC0 : r © 0.9329¥ and also closely correlated with the dose per 37.5 mg 75 mg 150 mg ¤ ¥¤ © © unit BW mg/kg Cmax:r 0.8257, AUC0®W:r 0.8455, Single-dose PK study in pediatric patients Fig. 3¥. N 12 13 Multiple-dose PK evaluation in pediatric pa- Sex male 8 9 tients: Steady state plasma trough roxatidine concen- female 4 4 ¤ ¥ Age ¤years¥ 9.8 + 2.1 10.3 + 2.7 trations Ctrough at the 2nd, 4th, and 8th week of repeated ¤range¥¤7®14¥¤6®14¥ Weight ¤kg¥ 34.68 + 9.34 33.70 + 11.51 Table 2. Pharmacokinetic parameters of roxatidine in pedia- ¤ 2¥ + + BSA m 1.128 0.157 1.135 0.248 tric patients and healthy adult volunteers Serum creatinine ¤mg/dL¥ 0.410 + 0.118 0.417 + 0.121 Single-dose PK study in healthy adult volunteers 37.5 mg 75 mg 150 mg N 888 Pediatric Healthy adult Pediatric Healthy adult Healthy adult Sex male 8 8 8 patients volunteers patients volunteers volunteers ¤ ¥ + + + Age years 30.3 7.3 37.5 7.0 33.4 7.0 N 12 8 13 8 8 Weight ¤kg¥ 63.46 + 5.51 65.14 + 8.47 63.73 + 8.36 + + + + + Cmax 354 131 158 20 530 148 329 54 629 67 BSA ¤m2¥ 1.755 + 0.066 1.769 + 0.133 1.765 + 0.133 ¤ng/mL¥ ¤ ¥a Serum creatinine ¤mg/dL¥ 0.794 + 0.060 0.781 + 0.141 0.824 + 0.102 Tmax h 2.0 2.5 3.0 3.0 2.0 Multiple-dose PK evaluation in pediatric patients 2.0®6.0 1.5®3.0 1.0®6.0 2.0®3.0 2.0®3.0 + + + + + N 615 AUC0®t 1,995 622 1,273 228 3,513 878 2,310 382 5,046 624 ¤ & ¥ Sex male 3 8 ng h/mL + + + + + AUC0®W 2,054 619 1,353 249 3,587 890 2,424 397 5,275 696 female 3 7 ¤ & ¥ ¤ ¥ + + ng h/mL Age years 8.2 2.0 10.8 2.0 ¤ ¥ + + + + + T1/2 h 4.6 1.1 5.6 0.3 4.2 0.9 5.0 0.6 5.0 0.4 ¤range¥¤6®12¥¤7®14¥ CL/F 19.6 + 5.1 28.6 + 5.3 22.4 + 6.9 31.8 + 6.0 28.8 + 3.5 ¤ ¥ + + Weight kg 23.33 3.44 38.63 5.64 ¤L/h¥ BSA ¤m2¥ 0.877 + 0.060 1.242 + 0.111 Vd/F ¤L¥ 134 + 55 229 + 41 138 + 73 232 + 62 208 + 29 Serum creatinine ¤mg/dL¥ 0.367 + 0.071 0.424 + 0.088 Mean + S.D. Mean + S.D. aUpper: median values, lower: range ¤min®max¥.

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

Fig. 2. The relationship between BSA or BW to CL/F and Vd/F in pediatric patients and healthy adult volunteers Closed circles, pediatric patients; open circles, healthy adult volunteers. (a) BSA and CL/F. Correlation coefficient ¦ 0.7882. (b) BW and 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 pediatric Table 4. The mean trough roxatidine concentrations (Ctrough) patients and healthy adult volunteers in the multiple-dose PK evaluation in pediatric patients

37.5 mg 75 mg 150 mg 37.5 mg 75 mg

Healthy Healthy Healthy a Pediatric Pediatric p value N 615 adult adult adult patients patients 26.8 volunteers volunteers volunteers 2nd week ¯ ¤n © 1¥ Pharmacokinetic parameters adjusted by BSA 24.9 + 8.9 65.4 + 43.9 4th week N 12 8 13 8 8 ¤n © 5¥¤n © 14¥ CL/F + + 17.3 + 3.5 16.2 + 2.8 19.7 + 3.6 17.9 + 2.3 16.4 + 1.9 0.0703 24.8 19.5 61.7 49.1 ¤L/h/m2¥ 8th week ¤n © 5¥¤n © 13¥ Vd/F 117 + 40 130 + 22 119 + 39 130 + 28 118 + 19 0.6426 ¤L/m2¥ Mean + S.D. ¤ng/mL¥. Pharmacokinetic parameters adjusted by BW N 12 8 13 8 8 CL/F 0.58 + 0.13 0.45 + 0.08 0.68 + 0.14 0.49 + 0.05 0.46 + 0.07 0.5985 ¤L/h/kg¥ Vd/F A number of assay methods have been developed for the 3.90 + 1.31 3.63 + 0.67 4.13 + 1.24 3.55 + 0.71 3.31 + 0.63 0.9392 ® ¥ ¤L/kg¥ determination of roxatidine in biological samples.13 15 Mean + S.D. However, blood sample volumes for pediatric studies should aAnalysis of covariance. be minimized, and reduction of sample volumes was necessary. Therefore we developed a highly sensitive assay for the determination of roxatidine concentration. The necessary doses were almost constant in children ¤Table 4¥.A plasma volumes for each determination was reduced to simulation of roxatidine concentration profile after multiple 50 µL compared to 1 mL in adult trials previously per- doses was conducted using the superposition method with formed, and our analytical method provided the advantages the mean plasma roxatidine concentrations in the single-dose of high sensitivity with a limit of quantification ¤LOQ¥ of PK study in pediatric patients. The results of the simulation 1 ng/mL. The obtained PK parameters this time in healthy were consistent with the measured Ctrough at the respective adult volunteers were comparable with those reported time ¤Fig. 4¥. recently.14,15¥ C and AUC ®W in the pediatric patients following 37.5 Discussion max 0 or 75 mg were higher than those in the healthy adult The PK profile of roxatidine capsule in pediatric patients volunteers following the same doses, while Vd/F and CL/F aged between 6 and 14 years was characterized and were lower than those in the healthy adult volunteers. An compared to that in healthy adult volunteers. investigation of the relationships of Vd/F to BSA or BW

Fig. 3. The relationship between dose adjusted by BSA or BW to Cmax or AUC0–W in pediatric patients and healthy adult volunteers Closed circles, pediatric patients; open circles, healthy adult volunteers; solid line, regression line. (a) Dose adjusted by BSA (mg/m2)and

Cmax. Correlation coefficient ¦ 0.8406. (b) Dose adjusted by BW (mg/kg) and Cmax. Correlation coefficient ¦ 0.8257. (c) Dose adjusted by BSA 2 (mg/m )andAUC0–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-dose PK study and multiple-dose profiles simulated from single-dose PK study data The multiple-dose data in pediatric patients were simulated with the superposition method using the mean plasma concentrations of roxatidine from the single-dose PK study in pediatric patients weighing less than 30 kg who took a 37.5 mg roxatidine capsule (n ¦ 4) or weighing 30 kg or morewhotook75mg(n ¦ 6). Ctrough in the multiple-dose PK evaluation in pediatric patients is shown. Solid line, 37.5 mg roxatidine capsule; broken line, 75 mg; open circles, Ctrough (mean + S.D.) 37.5 mg at the second week (n ¦ 1),atthe4thweek(n ¦ 5), and at the 8th week (n ¦ 5); closed circles, Ctrough (mean + S.D.)75mgatthe4thweek(n ¦ 14) and at the 8th week (n ¦ 13). revealed close correlation. Vd/F of roxatidine in the pedia- the healthy adult volunteers, because Vd/F, CL/F adjusted tric patients and healthy adult volunteers were comparable by BSA or BW and also Tmax in the pediatric patients were when adjusted by BSA or BW. Similarly, CL/F in the similar to the adult values. pediatric patients and healthy adult volunteers were com- The close correlation of the Cmax and AUC0®W to the parable when adjusted by BSA or BW. The differences in dose per unit BSA ¤mg/m2¥ in the pediatric patients and fi Cmax and AUC0®W are therefore most likely attributable to healthy adult volunteers shows that the PK pro le of differences in body size between children and adults. The roxatidine capsule in pediatric patients is similar to the absorption and elimination processes of roxatidine capsule in profile in healthy adult volunteers. Similar results were pediatric patients do not appear to differ substantially from obtained for the dose per BW ¤mg/kg¥.

Roxatidine excretion is dependent on renal function. T1/2 Takahashi, Osaka General Medical Center: Hitoshi Tajiri, has been reported to be prolonged, and AUC was increased Osaka Medical Center and the Research Institute for in renal failure with low creatinine clearance. The dosage Maternal and Child Health: Shinobu Ida. 8¥ adjustment is necessary in renal failure. The pediatric References patients with renal dysfunction were excluded in our studies, and influence of decreased renal function could not 1¥ Tarutani, M., Sakuma, H., Shiratsuchi, K. and Mieda, M.: m ª ¤ be evaluated. As renal function ¤creatinine clearance¥ per Histamine H2-receptor antagonistic action of N- 3- 3- 1-piperidinylmethyl¥phenoxy«propyln acetoxyacetamide hydrochloride ¤TZU- BSA in children aged 2 years or older is reported to be 0460¥. Arzneim.-Forsch./Drug Res., 35: 703®706 ¤1985¥. 16¥ fi comparable to that in adults, the PK pro le of roxatidine 2¥ Miyasaka, K., Izumi, A., Sakuma, H., Mikami, T., Himori, N., capsules in children aged 6 years or older is expected to Ishimori, T., et al.: General pharmacological studies on TZU-0460, ® be similar to that in adults. This is consistent with the results a new H2-receptor antagonist. Jpn. Pharmacol. Ther., 13: 627 661 ¤ ¥ of our PK studies in pediatric patients and healthy adult 1985 . 3¥ Murdoch, D. and McTavish, D.: Roxatidine acetate. A review of volunteers. its pharmacodynamic and pharmacokinetic properties, and its The results of a simulation of plasma roxatidine con- therapeutic potential in peptic ulcer disease and related disorders. centrations after multiple doses based on the data of the Drugs, 42: 240®260 ¤1991¥. single-dose PK study in pediatric patients were consist- 4¥ Collins, J. D. and Pidgen, A. W.: Pharmacokinetics of roxatidine in ¤ ¥ ® ¤ ¥ ent with the measured trough levels in the multiple-dose PK healthy volunteers. Drugs, 35 Suppl. 3 :41 47 1988 . 5¥ Akutsu, R., Iwamura, S., Honma, S., Tsukamoto, K. and Kawabe, evaluation in pediatric patients. This means that the steady Y.: Metabolic fate of 2-Acetoxy-N-ª3-ªm-¤1-piperidinylmethyl¥- « « ¤ ¥ state was reached, and that accumulation of roxatidine in phenoxy propyl acetamide hydrochloride TZU-0460 ,aH2-recep- plasma did not occur after multiple doses. Accumulation tor antagonist ¤3¥. ¯Absorption and excretion in dogs¯. Jpn. with roxatidine multiple doses did not occur in adults, Pharmacol. Ther., 13: 1435®1443 ¤1985¥. ¥ either.17¥ 6 Shirota, K., Ueda, K., Fujikata, A. and Iwamura, S.: Inhibitory effect of roxatidine acetate on the drug metabolism by human Gastric acid secretion reaches a level similar to that in cytochrome P450 isozymes. Jpn. Pharmacol. Ther., 31: 363®366 18¥ adults by age 3 to 4 years. A pediatric pharmacodynamic ¤2003¥. ¤PD¥ study with gastric pH as an endpoint was conducted ¤to 7¥ Honma, S., Akutsu, R., Iwamura, S., Kawabe, Y. and Tsukamoto, be published elsewhere¥, and the results were comparable to K.: Metabolic fate of 2-Acetoxy-N-ª3-ªm-¤1-piperidinylmethyl¥- ¥ « « ¤ ¥ that in other clinical studies of healthy adult volunteers.19,20 phenoxy propyl acetamide hydrochloride TZU-0460 , a new H2- fi receptor antagonist ¤8¥ the metabolism in man. Pharmacometrics, 30: Therefore, PK and PD pro le of roxatidine in pediatric 555®563 ¤1985¥. patients aged 6 years or older appears to be similar to that 8¥ Takabatake, T., Ohta, H., Yamamoto, Y., Ishida, Y., Hara, H., fi in adults. Clinical ef cacy was observed in a phase 3 study Nakamura, S., et al.: Pharmacokinetics of TZU-0460, a new H2- as well. receptor antagonist, in patients with impaired renal function. Eur. J. ® ¤ ¥ In conclusion, this investigation of the PK profile of Clin. Pharmacol., 30: 709 712 1986 . 9¥ Tanaka, T., Yamashita, A. and Ichihara, K.: Reference Intervals roxatidine capsules in pediatric patients revealed the PK fi of Clinical Tests in Children Determined by a Latent Reference pro le in children to be similar to that in adults when the Value Extraction Method. J. Jpn. Pediatr. Soc., 112: 1117®1132 data were adjusted by BSA or BW. This investigation also ¤2008¥. showed that the optimal roxatidine capsule dosage can be 10¥ Honma, S., Akutsu, R., Iwamura, S. and Tsukamoto, K.: Meta- bolic fate of 2-Acetoxy-N-ª3-ªm-¤1-piperidinylmethyl¥phenoxy«- calculated according to the BSA or BW in patients aged 6 « ¤ ¥ propyl acetamide hydrochloride TZU-0460 , a new H2-recep- years or older. As the roxatidine capsule has a broad safety tor antagonist ¤5¥ the metabolism in serum and liver in vitro. margin, the clinical dosage can be conveniently determined Pharmacometrics, 30: 347®355 ¤1985¥. based on BW instead of BSA. Based on these data, the 11¥ Guidance for Industry: Bioanalytical Method Validation. US dosage of roxatidine approved by Pharmaceuticals and Department of Health and Human Services, Food and Drug ¤ ¥ Medical Devices Agency for the pediatric patients with acid- Administration, Center for Drug Evaluation and Research CDER , 2001. related disease is 37.5 mg for those weighing less than 30 kg, 12¥ Du Bois, D. and Du Bois, E. F.: Tenth paper a formula to estimate and 75 mg for those weighing 30 kg or more. the approximate surface area if height and weight be known. Arch. Intern. Med., 17: 863®871 ¤1916¥. Acknowledgments: The authors thank all investigators 13¥ Iwamura, S., Honma, S., Akutsu, R., Kawabe, Y. and Tsukamoto, ö K.: Metabolic fate of 2-Acetoxy-N-ª3-ªm-¤1-piperidinylmethyl¥- and investigators cooperators in the following sites. « « ¤ ¥ phenoxy propyl acetamide hydrochloride TZU-0460 , a new H2- Hamamatsu University School of Medicine: Mitsuyoshi receptor antagonist ¤1¥ absorption, distribution and excretion in Nakashima, Saiseikai Yokohamashi Tobu Hospital: Ayano rats. Pharmacometrics, 30: 299®320 ¤1985¥. Inui, Miyagi Childrenös Hospital: Daiki Abukawa, Maruyama 14¥ Shin, B. S., Choi, J. W., Balthasar, J. P., Hong, D. K., Kim, J. J. Hospital: Shogo Sesoko, Sapporo-Kosei General Hospital: and Yoo, S. D.: Determination of roxatidine in human plasma by Mutsuko Konno, National Center for Child Health liquid chromatography/electrospray mass spectrometry and appli- cation to a clinical pharmacokinetic study. Rapid Commun. Mass and Development: Katsuhiro Arai, Tokyo Metropolitan ® ¤ ¥ ö Spectrom., 21: 329 335 2007 . Children s Medical Center: Yuko Hamasaki, Kanagawa 15¥ Ryu, J. H., Choi, S. J., Lee, H. W., Choi, S. K. and Lee, K. T.: Childrenös Medical Center: Masato Shinkai, Eihiko Quantification of roxatidine in human plasma by liquid chromatog-

raphy electrospray ionization tandem mass spectrometry: applica- B. F. ¤eds.¥: Nelson Textbook of Pediatrics. 18th ed. Philadelphia tion to a bioequivalence study. J. Chromatogr., B, 876: 143®147 ¤PA¥, Saunders Elsevier, 2007, pp. 1572®1575. ¤2008¥. 19¥ Kihira, K., Yoshida, Y., Kasano, T., Hirose, M., Sato, K., 16¥ Yaffe, S. J. and Aranda, J. V.: Neonatal and Pediatric Hashimoto, M., et al.: Effects of different dosages of roxatidine on Pharmacology. Therapeutic Principles in Practice. Third Edition. 24hrs intragastric pH. Nippon Naika Gakkai Zasshi, 78: 968®969 Philadelphia, Lippincott Williams & Wilkins, 2004, pp. 20®31. ¤1989¥. 17¥ Hasegawa, Y., Osawa, H., Mine, T., Honma, S., Akutsu, R. 20¥ Nakamura, T. and Shirai, H.: Investigation of acid inhibitory effect and Kawabe, Y.: Clinical pharmacology of TZU-0460, a novel of roxatidine acetate hydrochloride 75mg by 24hr intragastric pH ® ¤ ¥ Histamine H2-antagonist. Jpn. Pharmacol. Ther., 13:85 97 1985 . monitoring, comparison between daytime and nighttime admin- 18¥ Kliegman, R. M., Behrman, R. E., Jenson, H. B. and Stanton, istration. Jpn. Pharmacol. Ther., 25: 1463®1469 ¤1997¥.