ORIGINAL RESEARCH ARTICLE

Pediatr Drugs 2012; 14 (6): 401-409 1174-5878/12/0006-0401/$49.95/0 Adis 2012 Springer International Publishing AG. All rights reserved.

Pharmacokinetics of Olmesartan Medoxomil in Pediatric Patients with Hypertension

Thomas G. Wells,1 Douglas L. Blowey,2 Janice E. Sullivan,3 Jeffrey Blumer,4 Joseph R. Sherbotie,5 SaeHeum Song,6 Shashank Rohatagi,6 Reinilde Heyrman6 and Daniel E. Salazar6
1 2 3 4 5 6 Arkansas Childrens Hospital, University of Arkansas for Medical Sciences, Little Rock, AR, USA The Childrens Mercy Hospital, University of Missouri-Kansas City, Kansas City, MO, USA University of Louisville, Kosair Childrens Hospital, Louisville, KY, USA The University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA University of Utah School of Medicine, Salt Lake City, UT, USA Daiichi Sankyo, Inc., Parsippany, NJ, USA

Abstract

Background: The prevalence and importance of hypertension in younger patients is becoming increasingly recognized; however, only a limited number of clinical trials have been conducted in the pediatric population. Objective: The aim of this study was to characterize the pharmacokinetics and short-term safety of olmesartan medoxomil in children and adolescents with hypertension. Methods: An open-label, multicenter, single-dose study was conducted in children and adolescents aged 12 months16 years who were receiving treatment for hypertension or, if not currently treated for hypertension, had either a systolic blood pressure (SBP) or diastolic blood pressure (DBP) 95th percentile, or SBP or DBP 90th percentile if diabetic or with a family history of hypertension. Patients were stratified by age: 1223 months (Group 1; none enrolled), 25 years (Group 2; n = 4), 612 years (Group 3; n = 10), and 1316 years (Group 4; n = 10). All patients received a single oral dose of olmesartan medoxomil based on the individuals age and bodyweight. Patients aged <6 years received an oral suspension of olmesartan medoxomil at a dose of 0.3 mg/kg of bodyweight (not to exceed 20 mg), those aged 6 years who weighed 35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. Results: In Groups 2, 3, and 4, the weight-adjusted apparent total body clearance (CL/F) of olmesartan medoxomil was 0.100 0.034, 0.062 0.020, and 0.072 0.022 L/h/kg, respectively, and the weightadjusted apparent volume of distribution (Vd/F) was 0.32 0.16, 0.33 0.14, and 0.49 0.23 L/kg, respectively. CL/F and Vd/F in Groups 3 and 4 were not significantly different. Statistical comparisons between Groups 3 or 4 and Group 2 were not performed due to the small sample size of Group 2 (n = 4). Plasma elimination half-life and time to maximum plasma concentration were similar across the three groups. In Groups 3 and 4, considerable interindividual variability was seen in maximum plasma concentration (Cmax), area under the curve (AUC) from time zero to the last measurable concentration, and apparent clearance, with AUC and Cmax approximately 30% greater in Group 3. Four of 24 (16.7%) patients experienced treatment-emergent adverse events that were all mild in severity and considered not drug-related. No deaths, serious adverse events, or discontinuations due to adverse events occurred in the study. Conclusions: Olmesartan medoxomil was well tolerated and demonstrated a pharmacokinetic profile in pediatric patients similar to that of adults when adjusted for body size. Trial Registration: ClinicalTrials.gov identifier: NCT00151814

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Background The long-term health risks of hypertension in adults are well established, as are the benefits of lowering blood pressure (BP) by pharmacologic modulation of the renin-angiotensin system (RAS).[1-3] The prevalence and importance of hypertension in younger patients is becoming increasingly recognized, an example of which is the most recent report from the National High Blood Pressure Education Program that indicated as many as 3% of the pediatric and adolescent population have hypertension.[4] In addition, the Chronic Kidney Disease in Children Study has shown that 37% of these patients had elevated BP, many of whom were not being treated with antihypertensive therapy.[5] While a number of studies have been performed in adults supporting the safety and efficacy of RAS modulators as antihypertensive agents, fewer clinical trials have been conducted in the pediatric population.[6-12] Olmesartan medoxomil is an orally available angiotensin type II receptor blocker (ARB) approved for the treatment of hypertension in children and adolescents (aged 616 years), as well as in adults. Results from the completed Assessment of Efficacy and Safety of Olmesartan in Pediatric hypertension (AESOP) clinical trial[13] assessed the BP-lowering efficacy and safety of olmesartan medoxomil in children and adolescents aged 616 years.[14] Pediatric patients were stratified by weight to receive low-dose (2.5 or 5 mg) or high-dose (20 or 40 mg) olmesartan medoxomil daily for 3 weeks. Efficacy results demonstrated a dose-dependent, statistically significant reduction in sitting trough systolic BP (SBP) and diastolic BP (DBP). Several clinical trials have shown that, in adults, olmesartan medoxomil has the therapeutic benefits of once-daily dose administration, 24-hour BP control, and a safety and tolerability profile similar to that of placebo.[15] In addition, olmesartan medoxomil has a low potential for clinically significant drugdrug interactions. The objective of the present study was to evaluate the pharmacokinetics and short-term safety of olmesartan medoxomil to aid appropriate dose selection for the treatment of hypertension in children and adolescents.

informed consent forms were approved by the local institutional review boards (IRBs), and written informed consent and authorization were obtained from each patients parent or legal guardian prior to performing any study-related events or procedures. Patient assent was obtained according to the local IRB guidelines.
Patient Selection

Methods This was a multicenter, open-label, single-dose study conducted in six centers in the US. The trial was conducted in compliance with the ethical principles set forth in the Declaration of Helsinki and with the International Conference on Harmonisation E6 Guideline for Good Clinical Practices, as described in the US FDA Regulations (21 Code of Federal Regulations Parts 50, 56, and 312). The study protocol and
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Children and adolescents aged 12 months16 years who were either receiving drug therapy for hypertension at the time of enrollment or who had untreated hypertension were eligible for study entry. All eligible patients had to be hypertensive, which was defined as having a sitting cuff SBP or DBP at or above the 95th percentile for their age, sex, and height. Patients with diabetes mellitus or a family history of hypertension were eligible if their SBP or DBP was at or above the 90th percentile.[4] Patients were required to have a glomerular filtration rate 30 mL/min/ 1.73 m2, as estimated by the Schwartz equation.[16] All females of childbearing potential were required to have negative serum pregnancy tests and, if sexually active, to use an acceptable method of birth control. Exclusion criteria encompassed the presence of any clinically significant medical condition other than hypertension and included cardiac, gastrointestinal, hematologic, hepatic, neurologic, or pulmonary disorders. Participants were allowed to take calcium channel blockers, ACE inhibitors, ARBs other than olmesartan medoxomil, b-blockers, or hydrochlorothiazide alone, or in combination as concomitant therapy, provided the dosage was unchanged during the study. The parent/guardian was instructed to withhold all antihypertensive medications on the day that the patient was scheduled to receive the study drug. All other routine medications (i.e. non-antihypertensive) were to be administered at least 2 hours before or 4 hours after administration of the study drug. If the patient normally received antihypertensive agents on a schedule that was more frequent than once daily, then doses scheduled to be administered after the missed doses could be administered on the patients usual schedule, as long as they were given at least 4 hours after the study drug and the subject did not have symptomatic hypotension. Patients were stratified by age into four groups: Group 1 (1223 months, inclusive), Group 2 (25 years, inclusive), Group 3 (612 years, inclusive), and Group 4 (1316 years, inclusive).
Preparation and Dosing

Olmesartan medoxomil 20 and 40 mg doses (Benicar; Daiichi Sankyo, Inc., Parsippany, NJ, USA) were provided to
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each study site. All patients received a single oral dose of olmesartan medoxomil based on each individuals age and bodyweight. Children aged <6 years received an oral suspension at a dose of 0.3 mg/kg of bodyweight, not to exceed 20 mg. Patients aged 6 years who weighed 35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. The suspension was also offered as an alternative to children aged 6 years who were unable to swallow tablets without dose adjustment, as a previous investigation in adults showed bioequivalence between oral suspension and tablet formulations of olmesartan medoxomil (data on file, Daiichi Sankyo, Inc.). A pharmacist at or near each study site prepared the liquid suspension at concentrations of 0.5 mg/mL and 4.0 mg/mL by combining olmesartan medoxomil 20 mg tablets with a commercial oral syrup (Ora-Sweet; Paddock Laboratories, Inc., Minneapolis, MN, USA), a commercial suspension vehicle (Ora-Plus; Paddock Laboratories, Inc., Minneapolis, MN, USA), and purified water according to a standard protocol. The suspension was administered with a calibrated oral syringe delivery system. At dosing time, the syringe was inverted to thoroughly mix the suspension, and the contents dispensed directly into the patients mouth. Water was offered after the suspension was administered. Tablets of olmesartan medoxomil were administered orally in the clinic with up to 240 mL of water.
Study Design

mediately prior to dosing on day 1), and at 1, 2, 4, 8, 12, 24, and 48 hours postdose. Plasma was split into two equal aliquots and stored at -20C. For those children able to cooperate, all voided urine was collected at intervals of 06, 612, and 1224 hours postdose. After collection, urine volume for each interval was recorded, thoroughly mixed, split into two equal aliquots, and frozen at -20C. A validated high-performance liquid chromatography-tandem mass spectrometry method was used to assay plasma and urine samples for drug concentrations. Additional details of sample handling and analysis are published elsewhere.[17]
Pharmacokinetics and Data Analysis

Patients were screened for eligibility within 21 days of dosing. During this time, medical history was recorded, a physical examination was performed, and BP was measured. At the screening visit, the parent or legal guardian was informed to withhold all antihypertensive medications on the day that the patient was scheduled to receive olmesartan medoxomil. All other medications were to be administered at least 2 hours before, or 4 hours following, administration of olmesartan medoxomil. Patients were given a single oral dose of olmesartan medoxomil at least 1 hour following a light breakfast on day 1. Serial blood samples were collected for 48 hours. Adverse events (AEs) and vital signs, including BP, were monitored predose and through 48 hours postdose. Other safety assessments included physical examinations, clinical laboratory testing, and electrocardiographic testing.
Sampling Schedule and Specimen Handling

Each patient had a 1 mL blood sample drawn for pharmacokinetic evaluation. Samples were collected at predose (imAdis 2012 Springer International Publishing AG. All rights reserved.

Pharmacokinetic parameters were calculated from plasma values of olmesartan using non-compartmental methods and included area under the drug concentration-time curve calculated using linear trapezoidal summation from time zero to time t (48 hours) [AUC0t], the time of the last measurable concentration; area under the drug concentration-time curve from time zero to infinity (AUC0inf) calculated as AUC0t + Ct/Kel, where Kel represents apparent terminal elimination rate constant and Ct represents the last observed concentration; maximum observed plasma drug concentration (Cmax); time to reach Cmax (tmax); elimination half-life (t) calculated as natural logarithm of 2 [ln(2)]/Kel; Kel calculated by linear regression of the terminal linear portion of the log concentration-time curve; apparent oral total body clearance (CL/F) calculated as (dose/1.25)/AUC0inf, where 1.25 is the ratio of the molecular weight of olmesartan medoxomil to that of olmesartan; and apparent oral volume of distribution (Vd/F) calculated as (1/Kel) CL/F. Renal clearance was calculated using olmesartan concentrations in the urine and plasma using the following formulas: renal clearance (CLR) = [Ae/AUCt], where Ae represents the total amount of olmesartan excreted in urine over all collection periods and AUCt represents the area under the drug concentration curve for the time periods of collection. Descriptive statistics, including mean, standard deviation, and coefficient of variation, were calculated by age group for all pharmacokinetic parameters. Pharmacokinetic parameters estimated in subgroups of children and adolescents were compared with similar values from prior studies in adults, and calculated using WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, USA) for plasma data and S-PLUS 8 (Insightful Corporation, Seattle, WA, USA) for urine data. Missing or unusable concentrations were removed from the data set, and concentrations that were below the quantifiable

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limit were set to zero. Distributions of pharmacokinetic parameters were assessed by visual inspection of histograms, density functions, and box-and-whisker plots. For data that had a lognormal distribution, between-group comparisons were performed using one-way analysis of variance (ANOVA) after logarithmic transformation. The point estimates of the geometric mean ratios relative to Group 4 (age 1316 years) and corresponding 90% confidence intervals (CIs) were obtained using the least-squares mean difference between groups and the 90% CIs from the ANOVA. For data that were not lognormal, the point estimates of the geometric mean ratios relative to Group 4 and corresponding 90% CIs were obtained using resampling. Between-group comparisons for the pharmacokinetic parameters of Groups 13 versus Group 4 were planned; however, due to the lack of enrollment in Group 1 (age 1223 months), between-group comparisons were not assessed for this age group. Furthermore, even though some between-group comparisons are reported for Group 2 (age 25 years), due to the limited enrollment of this group, statistically valid between-group comparisons are limited to Group 3 (age 612 years) versus Group 4 (age 1316 years). Results
Patient Characteristics

Table I. Baseline demographics and characteristics of all enrolled subjects Attribute Group 2 25 yearsa (n = 4) Group 3 612 years (n = 10) Group 4 1316 years (n = 10) All groups combined (n = 24)

Age [years] Mean (SD) Median MinMax Individual Sex [n (%)] Male Female Race [n (%)] White Black 2 (50) 2 (50) 2 (20) 9 (90) 5 (50) 5 (50) 9 (38) 16 (67) 1 (25) 3 (75) 5 (50) 5 (50) 5 (50) 5 (50) 11 (46) 13 (54) 5 (1) 5 45 5/5/4/5 10 (1) 11 811 15 (1) 15 1316 11 (4) 11 416

Ethnicity [n (%)]b Hispanic Height [cm] Mean (SD) Median MinMax Individual Weight [kg] Mean (SD) Median MinMax 32 (16) 30 1852 39/52/18/20 70 (21) 71 33102 86 (30) 89 43136 71 (30) 66 18136 117 (9) 118 106126 122/126/106/113 152 (9) 152 134163 166 (10) 166 148178 152 (19) 156 106178 1 (25) 1 (10) 0 (0) 2 (8)

Overall, 33 patients were screened for the study at six US centers, and a total of 24 patients were enrolled and completed the study. Nine of the 33 patients had screen failures and were not randomized for the following reasons: did not meet inclusion criteria (n = 4), subject request (n = 3), and other (n = 2). There were no patients enrolled in Group 1 (age 1223 months), four patients were enrolled in Group 2 (age 25 years), and 10 patients each were enrolled in Groups 3 (age 612 years) and 4 (age 1316 years) [table I]. All patients in Group 4 and nine patients in Group 3 received olmesartan medoxomil 40 mg. One patient in Group 3 received olmesartan medoxomil 20 mg. The four patients in Group 2 received olmesartan medoxomil 5, 6, 12, and 16 mg based on bodyweight (0.3 mg/kg of olmesartan medoxomil). A demographic summary is provided in table I. The mean age of the 24 patients was 11 years (range 416 years), there were 11 males and 13 females, and the majority of patients (67%) were Black and of non-Hispanic ethnicity. Mean body mass index (BMI) for the total cohort was 29 kg/m2. In Groups 2, 3, and 4, the numbers of patients with a normal BMI (BMI below the 85th percentile) were 2, 1, and 3, respectively, the
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Individual

Body mass index [kg/m2] Mean (SD) Median MinMax Individual 23 (8) 21 1633 26/33/16/16 30 (8) 32 1843 31 (10) 34 1845 29 (9) 32 1645

a Caution is needed for statistical interpretation for Group 2 because of the small sample size (n = 4); therefore, data for individual patients are also presented. b More than one race could be checked. Max = maximum; Min = minimum.

numbers of patients at risk of obesity (BMI in the 85th95th percentile) were 0, 1, and 1, and the numbers of patients considered obese (BMI above the 95th percentile) were 2, 8, and 6.[18] Eighteen out of 24 study patients had a family history of hypertension, and 21 out of 24 patients had primary hypertension. The mean dose administered was 0.3 mg/kg in Group 2, 0.57 0.12 mg/kg in Group 3, and 0.52 0.20 mg/kg in Group 4. All patients, with the exception of one patient in Group 3 (age 612 years), were receiving one or more concomitant
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medications. The most frequently used concomitant medications (not including antihypertensive agents) were corticosteroids and b-agonists administered for the treatment of asthma. Antihypertensive agents taken by study participants included amlodipine besylate (n = 6), nifedipine (n = 1), valsartan (n = 3), atenolol (n = 1), metoprolol tartrate (n = 1), enalapril (n = 3), and hydrochlorothiazide (n = 1).
Pharmacokinetics

The plasma concentration-time profiles of olmesartan for the three groups are shown in figure 1. Mean Cmax of olmesartan medoxomil was observed between 2 and 3 hours in all three age groups. Pharmacokinetic parameters for Groups 24 are shown in table II. Caution is required in the interpretation of the pharmacokinetic parameters in the youngest age group because of the limited sample size. For this reason, individual pharmacokinetic variables are provided as well as summary statistics for Group 2. There was considerable interindividual variability in the Cmax, AUC0t, and CL/F in Groups 3 and 4 (table II). The AUC and Cmax in Group 3 were approximately 30% greater than in Group 4. This may be attributed, in part, to the higher mean weight-adjusted dose in Group 3 (table I). Linear regression plots of weight-adjusted CL/F or Vd/F versus age are shown in figures 2 and 3. The mean CL/F corrected for bodyweight was similar between all age groups with a CL/F of 0.062, 0.072, and 0.073 L/h/kg for Groups 2, 3, and 4, respectively. There were no statistically significant differences in weight-adjusted CL/F
1200 Olmesartan plasma concentration (ng/mL)

between Groups 3 and 4 (p = 0.284). The mean Vd/F corrected for bodyweight was similar between all groups. Mean Vd/F was approximately 50% higher in Group 4 than in Group 3 (0.49 vs 0.33 L/kg, respectively); however, this difference was not statistically significant (table II). These results indicate that the differences in CL/F and Vd/F among the three age groups correspond to the proportional differences in bodyweights among these age groups. As expected, the t and tmax of olmesartan medoxomil were not associated with bodyweight or weight-adjusted dose, and remained relatively constant among the different age groups (table II). As shown in figure 4, a linear regression plot of t versus age demonstrates that elimination does not appear to be age-related. With the exception of one patient, the fraction of an administered dose excreted in urine ranged from 3.2% to 14.2%. The patient whose urinary recovery fell well outside this range (48%) was in Group 3 and was receiving concomitant hydrochlorothiazide (25 mg daily; table III). There were no other patients receiving concomitant hydrochlorothiazide. The CLR of olmesartan medoxomil in Group 3 (0.0067 0.0037 L/h/kg) was similar to that in Group 4 (0.0058 0.0032 L/h/kg). There were no statistically significant differences between groups in urine pharmacokinetic parameters.
Safety

In total, 4 of the 24 patients (16.7%) experienced treatmentemergent AEs; however, none of these treatment-emergent AEs
Group 2 (age 25 y) Group 3 (age 612 y) Group 4 (age 1316 y)

1000

800

600

400

200

0 0 4 8 12 16 20 28 24 Time (h) 32 36 40 44 48

Fig. 1. Olmesartan plasma concentration-time profiles by age group following single dosing with olmesartan medoxomil. The mean dose administered was 0.3 mg/kg in Group 2, 0.57 0.12 mg/kg in Group 3, and 0.52 0.20 mg/kg in Group 4.
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Table II. Plasma pharmacokinetic parameters of olmesartan AUC0t (ng/mL h)

Dose (min/max; mg/kg)

0.040 0.098 0.168 0.075 0.095 (0.0400.168) 0.054 948 238 0.0 5.6 0.033 0.165 2614 (16933649) 474 (307826) 2 (22) 9.4 (4.117.1) 0.101 (0.0670.133) 1935 393 2 9.2 0.125 0.292 0.321 (0.1320.533) 1693 307 2 4.1 0.133 0.132 3178 369 2 7.0 0.077 0.325 3649 826 2 17.1 0.067 0.533

Kel (L/h)

AUC01 (ng/mL h)

Cmax (ng/mL)

tmax (h)

t (h)

CL/F (L/h/kg unless otherwise specified)

Vd/F (L/kg unless otherwise specified)

Group 2 (25 years; n = 4)a 3476 3153 1671 1911 2553 (16713476) 895

Subject 1

0.3

Subject 2

0.3

Subject 3

0.3

Subject 4

0.3

Mean (range)

SD

Group 3 (612 years; n = 10) 7874 (369913 046) 2913 0.029 2913 451 1.3 2.4 1.9b 0.090 (0.0610.154) 7988 (382313 113) 1227 (4151821) 2.8 (1.04.0) 8.4 (4.511.4) 4.3b (2.08.4) 50.9c (19.076.4) 20.7c

Mean (range)

0.57

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(0.39/0.75)

SD

0.12

Normalizedd [mean (range)] 7442 (468412 774) 3031 3047 365 7553 (484112 839) 1124 (5261783)

0.062 (0.0320.087) 0.020

0.330 (0.1400.530) 0.140

SD

Group 4 (1316 years; n = 10) 5851 (253510 062) 2083 0.016 2130 262 1.1 0.079 (0.0570.105) 5982 (259810 300) 895 (3351239) 2.5 (1.04.0) 9.1 (6.612.2) 1.9 6.1b (3.112.3) 2.6b 81.3c (41.4175.1) 42.1c

Mean (range)

0.52

(0.29/0.93)

SD

0.20

Normalizede [mean (range)] 6085 (35458438) 1747 1762 284 6218 (35688606) 942 (5481401)

0.072 (0.0480.116) 0.020

0.490 (0.2381.012) 0.230

SD

Total cohort 3664 (16717338) 1440 1451 3732 (16937376) 573 (3021024) 199 0.073 (0.0320.133) 0.026 0.395 (0.1321.012) 0.197

Normalizedf [mean (range)]

SD

a Caution is needed for statistical interpretation for Group 2 because of the small sample size (n = 4).

b Liters per hour.

Liters.

d Data normalized to 0.57 mg/kg.

e Data normalized to 0.52 mg/kg.

Data normalized to 0.3 mg/kg. Wells et al.

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AUC01 = area under the drug concentration-time curve from time zero to infinity; AUC0t = area under the drug concentration-time curve from time zero to time t; CL/F = apparent total body clearance; Cmax = maximum observed plasma drug concentration; Kel = apparent terminal elimination rate constant; max = maximum; min = minimum; t = terminal elimination half-life; tmax = time to reach Cmax; Vd/F = apparent volume of distribution.

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0.20

Intercept = 0.1025 Slope = 0.0026 P = 0.0629

0.15 CL/F (L/h/kg)

0.10

0.05

0 0 4 8 Age (y) 12 16

Fig. 2. Linear regression plot of weight-adjusted apparent total body clearance (L/h/kg) vs age. CL/F = apparent total body clearance.

were considered drug-related all were mild in severity, and all patients recovered without treatment. One patient in Group 2 experienced headache and fatigue, while somnolence, diarrhea, and abdominal pain (n = 1 each) were reported in Group 3. No patient experienced hypotension following a single dose of olmesartan medoxomil. There were no deaths, serious AEs, or study discontinuations due to AEs. One patient in Group 4 had an abnormal urinalysis (high white blood cell count). There were no trends or clinically meaningful changes in hematology, serum chemistry, or urinalysis parameters during the study. Discussion Information regarding the pharmacokinetic profile of a drug in any intended patient population is essential for guiding proper dosing. The objective of the present study was to characterize the pharmacokinetic characteristics of olmesartan medoxomil for the first time in pediatric patients with hypertension. A total of 24 hypertensive children and adolescents between 4 and 16 years of age were evaluated. The study design allowed for enrollment of children and adolescents aged 12 months16 years to be distributed in four different age groups; however, no children aged <2 years were enrolled, and thus the results were derived from three of the specified age groups: Group 2 (25 years), Group 3 (612 years), and Group 4 (1316 years). It is noteworthy that although patients were dosed based on bodyweight within each age group, statistical analyses of data in this study were not based on body mass as a continuum; rather, similar to other pediatric pharmacokinetic studies, analyses were performed for each individual age group, i.e. Group 2, 3, or 4.[12,19] Although bodyweight is an important
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consideration in pediatric pharmacokinetic studies, it is equally true from a clinical perspective that age-related developmental differences in pharmacokinetics and pharmacodynamics are known to exist, and these differences vary in conjunction with changes in age.[20,21] Children in Group 2 received a single olmesartan medoxomil dose of 0.3 mg/kg, whereas those in Groups 3 and 4 received a single dose of either olmesartan medoxomil 20 or 40 mg depending on the individuals bodyweight. As would be expected, Cmax correlated with the weight-adjusted dose, suggesting that the extent of absorption does not markedly differ between groups. There were no differences in tmax between the three groups, suggesting that the rate of absorption is similar across the age range that was studied. The tmax of olmesartan occurred between 2.5 and 3 hours in Groups 3 and 4, which is in close agreement with previously reported values in adults (1.5 2.0 hours).[17,22] The older children and adolescents received a higher dose of olmesartan medoxomil on a weight-adjusted basis than those in the youngest age group (approximately 2-fold greater). This difference is reflected in the larger AUC values in the two older age groups compared with the youngest group. Another possible explanation for the difference in AUC between younger and older children is the potential for more rapid clearance in the younger age group. However, the CL/F of olmesartan, adjusted for bodyweight, was not statistically different between Groups 3 and 4. The Vd/F also increased with increasing age and bodyweight; however, after correcting for bodyweight, there were no statistically significant differences between groups. The estimated Vd/F in children (0.320.49 L/kg) compares well with those from a study in healthy adults in which Vd/F was estimated to range from approximately 0.190.33 L/kg.[22]
0.12 Intercept = 0.2158 Slope = 0.0160 P = 0.1447

0.8 Vd/F (L/kg) 0.4 0 0 4 8 Age (y) 12 16

Fig. 3. Linear regression plot of weight-adjusted apparent volume of distribution (L/kg) vs age. Vd/F = apparent volume of distribution.
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The differences in CL/F and Vd/F among the three age groups correspond to the proportional differences in bodyweights among these same age groups. Similar t values across the three pediatric age groups suggest that the rate of accumulation of olmesartan medoxomil with multiple daily dosing will be similar. The mean fractional recovery of olmesartan in the urine was estimated to be approximately 813% in Groups 3 and 4, respectively, both of which are comparable to the previously reported estimate in adults (~10%).[22] The findings of this pharmacokinetic study are consistent with those reported for other orally acting ARBs, several of which are approved for use in pediatric patients. The pharmacokinetics of candesartan,[23,24] irbesartan,[19] losartan,[25] telmisartan,[26] and valsartan[12,27] have been studied in children and adolescents aged 116 years and are reported to be similar to those observed in adults. As with the present olmesartan study, the plasma pharmacokinetic profiles of candesartan[23] and irbesartan[19] were similar in children aged 612 years and those aged >12 years, and increasing age had minimal influence on the body-sizedependent clearance of valsartan.[27] No clinically significant AEs associated with drug administration were reported, and clinical laboratory findings generally remained within normal values. Data from the previously mentioned AESOP trial, which assessed the BP-lowering efficacy and safety of olmesartan medoxomil on the basis of bodyweight in children and adolescents aged 616 years with hypertension,[14] along with the present pharmacokinetic study data, support the use of olmesartan medoxomil at dosages of 1040 mg once daily in children with hypertension aged 616 years. Collectively, the results of these two trials demonstrate that olmesartan medoxomil ef-

Table III. Urine pharmacokinetic parameters of olmesartan Ae (mg) Group 2 (25 years; n = 4)a Patient 1 Patient 2 Patient 3 Patient 4 Mean Range SD 1086 1163 132 326 677 1321163 453.7 11.6 9.4 3.2 6.9 7.8 3.211.6 3.1 0.31 0.37 0.08 0.17 0.23 0.080.37 0.11 Fe (%) CLR (L/h)

Group 3 (612 years; n = 10) Mean Range SD 4017 74115 429 4158 12.8 4.648.2 12.8 0.48 0.091.23 0.31

Group 4 (1316 years; n = 10) Mean Range SD 2504 9044534 1206 7.8 2.814.2 3.8 0.53 0.121.4 0.39

a Caution is needed for statistical interpretation for Group 2 because of the small sample size (n = 4). Ae = total amount of olmesartan excreted in urine over all collection periods; CLR = renal clearance; Fe = fraction of dose recovered as olmesartan in urine.

fectively controls BP and is well tolerated in the pediatric population. Conclusions The results of the present study demonstrate that the CL/F and Vd/F of olmesartan are proportional to bodyweight and that the t and tmax of olmesartan are similar across all age groups and are independent of bodyweight in children and adolescents with hypertension. Pharmacokinetic parameters across the age spectrum of 416 years did not differ greatly from values previously reported in adults. Collectively, these findings suggest that it is reasonable to dose olmesartan medoxomil in children and adolescents on the basis of bodyweight rather than age. Acknowledgments
We acknowledge a grant from the Pediatric Pharmacology Research Unit Network for partially supporting the work performed at the Arkansas Childrens Hospital, Little Rock, AR, USA; University of Louisville, Louisville, KY, USA; Rainbow Babies and Childrens Hospital, Cleveland, OH, USA; Childrens Mercy Hospital, Kansas City, MO, USA; and the University of Utah, Salt Lake City, UT, USA. Daiichi Sankyo, Inc. provided support for this study. We would like to thank Radha Basavapathruni, MSPH, formerly employed by Daiichi
Pediatr Drugs 2012; 14 (6)

20

Intercept = 8.3397 Slope = 0.0474 P = 0.7666

15 t (h)

10

0 0 4 8 Age (y) 12 16

Fig. 4. Linear regression plot of terminal elimination half-life vs age. t = terminal elimination half-life.
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Sankyo, Inc., for involvement in study management, and Alan J. Klopp, PhD, and Blair Jarvis, MSc, of inScience Communications, Springer Healthcare, for providing medical writing support funded by Daiichi Sankyo, Inc. Thomas G. Wells, MD, served as an investigator for the study discussed in the article and received medical writing support, which were both supported by Daiichi Sankyo, Inc. Janice E. Sullivan, MD, received pharmaceutical support from Daiichi Sankyo, Inc. to conduct the study. Jeffrey Blumer, MD, received a grant from the National Institutes of Health (NIH), Pediatric Pharmacology Research Unit grant 3U10HDA3132313;B.NA, which is unrelated to the study discussed in this article. Joseph R. Sherbotie, MD, received pharmaceutical support from Daiichi Sankyo, Inc. to conduct the study but no direct financial support was provided to the contributors. Shashank Rohatagi, PhD, and Reinilde Heyrman, MD, were employed by Daiichi Sankyo, Inc., the sponsor of the study, at the time the study was conducted. SaeHeum Song, PhD, and Daniel E. Salazar, PhD, FCP, are employees of Daiichi Sankyo, Inc., the sponsor of the study. SaeHeum Song holds stock appreciation rights/restricted stock units and Daniel Salazar holds stock options for Daiichi Sankyo, Inc. Douglas L. Blowey, MD, has no conflicts of interest to disclose.

11. Shahinfar S, Cano F, Soffer BA, et al. A double-blind, dose-response study of losartan in hypertensive children. Am J Hypertens 2005 Feb; 18 (2 Pt 1): 183-90 12. Blumer J, Batisky DL, Wells T, et al. Pharmacokinetics of valsartan in pediatric and adolescent subjects with hypertension. J Clin Pharmacol 2009 Feb; 49 (2): 235-41 13. Daiichi Sankyo, Inc. Assessment of efficacy and safety of olmesartan medoxomil in children and adolescent patients with high blood pressure [ClinicalTrials.gov identifier NCT00151775]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials. gov [Accessed 2012 Jul 10] 14. Hazan L, Hernandez Rodriguez OA, Bhorat AE, et al. A double-blind, dose-response study of the efficacy and safety of olmesartan medoxomil in children and adolescents with hypertension. Hypertension 2010 Jun; 55 (6): 1323-30 15. Greathouse M. Olmesartan medoxomil-based therapy for the management of hypertension. Expert Rev Clin Pharmacol 2008; 1: 593-604 16. Schwartz GJ, Haycock GB, Edelmann Jr CM, et al. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976 Aug; 58 (2): 259-63 17. Rohatagi S, Lee J, Shenouda M, et al. Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination. J Clin Pharmacol 2008 Nov; 48 (11): 1309-22 18. Health [online]. Available from URL: http://www.health.com/health/static/ hw/media/medical/hw/h9991021.gif [Accessed 2012 Jul 10] 19. Sakarcan A, Tenney F, Wilson JT, et al. The pharmacokinetics of irbesartan in hypertensive children and adolescents. J Clin Pharmacol 2001 Jul; 41 (7): 742-9 20. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003 Sep 18; 349 (12): 1157-67 21. Rane A, Wilson JT. Clinical pharmacokinetics in infants and children. Clin Pharmacokinet 1976; 1 (1): 2-24 22. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol 2001 May; 41 (5): 515-27 23. Trachtman H, Hainer JW, Sugg J, et al. Efficacy, safety, and pharmacokinetics of candesartan cilexetil in hypertensive children aged 6 to 17 years. J Clin Hypertens (Greenwich) 2008 Oct; 10 (10): 743-50 24. Schaefer F, van de Walle J, Zurowska A, et al. Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age. J Hypertens 2010 May; 28 (5): 1083-90 25. Cozaar (losartan potassium tablets): prescribing information. Whitehouse Station (NJ): Merck & Co., 2010 26. Wells TG, Portman R, Norman P, et al. Safety, efficacy, and pharmacokinetics of telmisartan in pediatric patients with hypertension. Clin Pediatr (Phila) 2010 Oct; 49 (10): 938-46 27. Habtemariam B, Sallas W, Sunkara G, et al. Population pharmacokinetics of valsartan in pediatrics. Drug Metab Pharmacokinet 2009; 24 (2): 145-52

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Correspondence: Dr Thomas G. Wells, Arkansas Childrens Hospital, 1 Childrens Way, Little Rock, AR 72202, USA. E-mail: wellsthomasg@uams.edu

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Pediatr Drugs 2012; 14 (6)

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