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PEDIATRICS |
From Merck Research Laboratories, Rahway, New Jersey (Dr. Migoya, Dr. Hartford, Dr. Zhao, Dr. van Adelsberg, Dr. Tozzi, Dr. Knorr, Dr. Deutsch); Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (Dr. Kearns); and Departments of Pediatric and Pharmacology, University of Missouri-Kansas City, Kansas City, Missouri (Dr. Kearns).
Address for reprints: Elizabeth Migoya, PharmD, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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6 to < 24 months old to the 10-mg approved dose in adults. This was an open-label study in 32 patients. Population pharmacokinetic parameters included estimates of AUCpop, Cmax, and tmax. Results were compared with estimates from adults (10-mg film-coated tablet [FCT]). Dose selection criteria were for the 95% confidence interval (CI) for the AUCpop estimate ratio (pediatric/adult 10 mg FCT) to be within comparability bounds of (0.5, 2.00). The AUCpop ratio and the 95% CI for children compared with adults were within the predefined comparability bounds. Observed plasma concentrations were also similar. Based on systemic exposure of montelukast, a 4-mg dose of montelukast appears appropriate for children as young as 6 months of age.
Key Words: Montelukast • asthma • pediatrics • pharmacokinetics
Chronic asthma in children often begins in infancy or early childhood and is associated with inflammation of the airways11,12 and with the production of cysteinyl leukotrienes.13,14 It is recommended that treatment for asthma begin early to control inflammation and potentially reduce the deterioration of lung function over time.15 Currently, therapeutic options for anti-inflammatory controller therapy for small children are limited because of difficulties associated with drug administration (aerosol delivery systems) and concerns related to growth suppression produced by corticosteroids.16-18
Previous studies with montelukast have demonstrated an improvement in asthma symptoms in adult6 and pediatric7,8 patients. Since the clinical expression and pathology of asthma are similar in children and adults,15,19 it is reasonable to assume that providing a similar level of systemic exposure to montelukast in young children comparable to levels associated with efficacy in adults would result in a favorable clinical response. The strategy of the current study accomplished this comparison of exposures in children to those in adults. Such an approach obviated the need for more extensive and classical pharmacokinetic and/or dose-ranging studies of montelukast in very young children. To date, such an approach has been used successfully to establish the age-appropriate doses of montelukast that are both well tolerated and efficacious for pediatric patients 2 to 520 and 6 to 14 years of age.21
Treatment of asthma in the youngest patients is limited by the lack of age-appropriate formulations that are convenient to administer. A well-tolerated controller medication with proven efficacy that was easy to give to patients would meet the medical needs of children younger than 24 months old. This study determined an appropriate dose of a new formulation of montelukast oral granules using a population pharmacokinetic analysis of the drug following single-dose administration in asthmatic patients 6 to < 24 months old.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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6 months to <24 months of age who were between 6 and 15 kg total body weight and within the 5th to 95th percentile of height for weight. Patients had a history of physician-diagnosed asthma, including 3 discrete episodes of wheezing after 8 weeks of age with episodes separated by a symptom-free interval of at least 7 days or asthma-like symptoms (including but not limited to cough, wheezing, and shortness of breath) with a history of bronchiolitis requiring chronic anti-inflammatory controller therapy. Patients had to have been on solid food for at least 1 month and had to be in good health, including no evidence of pulmonary symptoms, prior to study entry. Patients were excluded if they had a clinically significant disease/condition other than asthma/reactive airway disease, surgery within 8 weeks, unresolved signs and symptoms of an upper respiratory tract infection, or an upper respiratory tract infection within 1 week of the study. Participants were also excluded if they had taken astemizole within 3 months; terfenadine, loratadine, and/or oral or parenteral corticosteroids within 14 days; theophylline within 10 days; or any oral ß-agonists within 24 hours prior to study drug administration or had received drugs or natural products associated with induction or inhibition of cytochrome P450 (CYP) enzyme metabolism within 1 month of study entry. Written informed consent, approved by the respective institutional review boards or ethical review committees for each investigational site, was obtained from the legally authorized representative of each patient.
During the study, patients were allowed to use inhaled albuterol, inhaled cromolyn, and inhaled corticosteroids if required. These medications were administered by a nurse or physician at the study site.
Study Design
This was a multicenter, open-label, single-dose population pharmacokinetic study performed at five study sites in the United States and in South America. Montelukast (4-mg oral granules) was administered to each patient with 1 tbs (approximately 15-18 g) of applesauce obtained from a single vendor. Patients were randomly assigned to one of two possible sampling schedules (A or B) (Table I). Blood samples for pharmacokinetic analysis (four samples each in schedule A and B, 3-mL volume each) were obtained from an indwelling venous cannula up to 24 hours after drug administration depending on patient assignment. At the discretion of the investigator, patients were admitted into the study unit on the evening preceding drug administration and remained until the 12-hour blood sample was obtained. Patients assigned to schedule B, requiring a 24-hour sample, were required to return to the study unit for this blood sample.
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These sampling schedules were selected based on the ability to accurately estimate the AUC of montelukast in adult subjects compared to the AUC determined from the complete disposition profile (13-point concentration-time curves). The two 4-point (1 predose and 3 postdose) samples minimized the amount of blood required for sampling in the pediatric age group studied. Each schedule was selected so that the time points bracketed the mean time of maximum observed plasma concentration (tmax) of 3.4 hours observed in the adult subjects and provided sufficient data to reliably estimate the apparent terminal elimination rate constant and the 24-hour postdose plasma concentration. A similar strategy was used to assess the pharmacokinetics of the 4-mg chewable tablet (CT) in 2- to 5-year-old patients.20
Dose Selection
A 4-mg dose was selected for evaluation in the current study based on a weighted linear regression of the plotted AUC versus weight from previous pharmacokinetic studies in adults (10-mg film-coated tablet [FCT]) and pediatric patients (4-mg and 5-mg CT) (Figure 1). The predicted mean AUC and 95% confidence band, based on a 4-mg dose, were within one standard deviation (SD) of the reference mean AUC0-
, except at the very low end of the weight range, where the upper boundary of the 95% confidence band was slightly greater than one SD above the reference. The predicted AUC values were obtained using 6-month to 24-month age-appropriate weights of 6 to 15 kg. Given the wide therapeutic index and to avoid underdosing, the 4-mg dose was selected as an estimate of the appropriate dose for pharmacokinetic evaluation in 6- to < 24-month-old asthmatic patients.
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Pharmacokinetics
Population pharmacokinetic modeling differs from the subject-specific modeling used in adult studies with montelukast. In population modeling, only one estimate for each pharmacokinetic parameter is found and represents the typical behavior of a group of subjects. The values obtained by subject-specific modeling and population modeling are not identical; however, since they are both estimates representing the same parameter, they are clinically comparable. The population pharmacokinetic approach in this study employed a nonlinear, mixed-effect, one-compartment model with first-order absorption and elimination fitted to the available montelukast plasma concentration-time data. This approach was based on the assumption of linear pharmacokinetics for montelukast previously observed in pediatric21 and adult patients.22 The pharmacokinetic model and its validation have been described elsewhere.23
Statistical Methods
The pharmacokinetic parameters estimated included the population AUC, as well as population estimates for Cmax and tmax. The apparent elimination half-life (t1/2) was estimated using a linear mixed-effects model and concentration at 24 hours postdose (C24 h) from the mean of the observed values for this parameter. The population estimate of apparent oral clearance (CL/F) was also determined using the nonlinear mixed-effects model. Adequacy of the 4-mg dose in young children was assessed by comparison of the AUCpop after administration of the oral granules in patients 6 to < 24 months to the AUCpop historical data following administration of a single 10-mg FCT of montelukast in adults—the optimum adult dose selected based on dose-ranging studies.22,24 The AUCpop was computed based on the population estimates of the above parameters and was compared with adult historical data analyzed similarly. The 95% confidence interval (CI) for the AUCpop ratios (pediatric/adult values) were calculated for 6- to < 24-month-old patients. Although not a prespecified primary endpoint, AUCpop ratios were also calculated for the subgroups 6 to < 12 months old and 12 to < 24 months old. The 95% CI for the AUCpop ratio (pediatric/adult) was then evaluated against the prespecified comparability bounds of (0.50, 2.00). No bounds were prespecified for the subgroup comparisons. After a determination of a normal distribution for AUCpop values, the natural logarithm of the values from the 4-mg oral granules were compared to the 10-mg FCT data using an unpaired, two-tailed test. The montelukast CL/F and elimination rate constant values were assumed to have log-normal distributions, each centered on a population mean, while the absorption rate constant was assumed to be the same across all subjects within a cohort. Instead of estimating these parameters for each subject, this population-modeling approach estimates the population mean based on the distributional assumption. Descriptive summary statistics were used to express the population pharmacokinetic parameters for montelukast in the study cohort. Safety and tolerability were evaluated by tabulating adverse experiences and by clinical assessment of laboratory data.
Safety Evaluations
Clinical laboratory tests (hematology and serum chemistry) were performed 36 hours prior to randomization, at 24 hours postdose, and again at 3 to 5 days postdose. A physical examination, including height and weight, was performed 36 hours prior to randomization and at the 3- to 5-day poststudy visit. All patients had laboratory safety tests collected within 36 hours prior to dosing on day 1 of the study, except for 1 patient who had tests at 48 hours prior to dosing. Vital sign measurements, including blood pressure, heart rate, respiratory rate, and oral or tympanic temperature, were evaluated 3 hours prior to administration of montelukast, four times during the 24-hour sampling period, and once again at the 3- to 5-day poststudy visit. Adverse experiences were monitored throughout the 24-hour study period and for 14 days following completion of treatment. Spontaneously reported adverse experiences were recorded by the investigator, who determined the severity and causal relationship to study medication.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
The AUCpop estimates for pediatric patients and adults are given in Table III. The AUCpop estimates were 3226.6 ng•h/mL after administration of a single 4-mg dose of the oral granules to 6- to < 24-month-old pediatric patients, as compared to 2569.0 ng•h/mL after administration of a single 10-mg dose of the FCT to adults. The AUCpop ratio for infants 6 to < 24 months of age compared to adults was 1.26, with a 95% CI of (1.02, 1.54); these values are well within the prespecified comparability bounds of (0.50, 2.00). The AUCpop ratios for the age-based subgroups also were contained within the comparability interval, although these criteria were not prespecified (Table III). The population estimate for CL/F for montelukast clearance was approximately 3-fold lower (p = 0.05) in pediatric patients (20.7 ± 1.6 mL/min) compared to the estimate for adults (64.9 ± 4.2 mL/min), consistent with similar AUC values despite a 2.5-fold difference in the dose (4 mg and 10 mg, respectively) (Table IV). There were no significant differences in montelukast CL/F between the age-specific subgroups 6 to < 12 months old and 12 to < 24 months old (Table IV). The population estimates for Cmax and tmax and the mean values for t1/2 and C24 h are included in Table V. The population estimate for Cmax was approximately 2-fold greater in the 6- to < 24-month-old group (514.4 ng/mL) as compared to the estimate from the adult population (279 ng/mL). The population average value for tmax demonstrated an absolute difference of approximately 1 hour earlier in pediatric patients compared to adults. Mean values for t1/2 were roughly comparable between the pediatric patient subgroups or between the entire pediatric patient cohort (3.4 h) and that from the adult reference population (4.1 h), with a trend suggestive of a slightly shorter t1/2 in the pediatric patients. The mean C24h values were similar between pediatric patients and adult subjects, despite the 2.5-fold lower difference in the absolute montelukast dose given to the pediatric patients (4 mg) as compared to the adult reference population (10 mg). Scatter plots of the individual estimates for the AUC, estimated from time 0 to infinity (AUC0-) from the pediatric patients, revealed no apparent association of AUC with either age or weight of the ranges of the patients enrolled in the study (data not shown).
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Population pharmacokinetic data for montelukast from the present investigation and from previously published studies conducted in children20,21 and adults22 were used to simulate systemic exposure as a function of age and formulation. Figure 2 illustrates a population fit of the montelukast plasma concentration-time data after administration of a single 4-mg dose of the oral granules to 6- to < 24-month-old patients, following administration of a single 4-mg CT to children 2 to 5 years old and after a single 10-mg FCT to adults. Plasma-concentration profiles after administration of montelukast as 4-mg oral granules or as 4-mg CT are similar, with a greater peak concentration observed for oral granules and CT formulations compared to 10-mg FCT in adults. The simulated trough (24 h postdose) plasma concentrations were comparable for the 10-mg FCT in adults, the 4-mg CT in 2- to 5-year-olds, and the 4-mg oral granules in the 6- to < 24-month-old patients (Figure 2).
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Tolerability and Safety
A total of 13 patients reported 22 adverse experiences. There were no serious adverse experiences related to montelukast. The most common adverse experience was diarrhea occurring in 6 children. There were three cases of diarrhea and two cases of somnolence of mild intensity that were judged by the investigator to be possibly or probably drug related. One serious adverse experience of dehydration occurred 7 days after drug administration. This case of dehydration was due to nausea and vomiting and was viewed by the investigator to be definitely not related to montelukast. Three patients had four mild laboratory adverse experiences not considered to be drug related. One of the 3 patients had an increase in blood urea nitrogen from 13 to 24 mg/dL. This patient had the one serious adverse experience of dehydration due to nausea and vomiting. One patient had a decrease in neutrophil count 24 hours after montelukast administration that was not associated with a clinical adverse experience. Another patient experienced a slight, clinically insignificant reduction in hemoglobin at the 24-hour postdose evaluation. There were no clinically significant changes in vital sign determinations in any patient through the entire study period. In general, a single 4-mg dose of the oral granule formulation of montelukast was well tolerated in pediatric patients ages 6 to < 24 months old.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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6 to < 24 months of age similar to that of the clinically effective 10-mg FCT in adults. Thus, examination of the AUCpop data lends pharmacokinetic support for the use of the 4-mg dose of oral granules in these young asthmatic patients.
Reports of asthma presenting early in life provided justification for the current study in infants.25,26 Similarities in the pathophysiology of asthma between pediatric and adult patients15,19 prompted the selection of the population pharmacokinetic dose-finding approach for montelukast in patients 6 to < 24 months of age that targeted a predefined comparability interval (0.50, 2.00). This interval was initially determined from classic studies that defined the exposure-response relationship for the drug.22 In addition, the population pharmacokinetic approach comparing the 90% CI of the AUCpop ratio with the (0.50, 2.00) interval was used for montelukast dose selection to support the 4-mg CT dose currently approved for 2- to 5-year-old patients with asthma.20
There were no apparent age-associated differences for the population pharmacokinetic parameters of montelukast within the experimental population and no clinically meaningful differences when data from the pediatric patients were compared to historical population pharmacokinetic data for adults (Tables III and V). The AUCpop for the 6- to < 24-month-old patients (3226.6 ng•h/mL) is approximately 25% greater than the adult estimate; however, montelukast has a wide therapeutic index,22,27 and unexpected toxicities would not be associated with this extent of systemic exposure in pediatric patients following the 4-mg dose. In addition, the pharmacokinetic profile (AUCpop) for 6- to < 24-month-old patients was similar to that for the 5-mg CT in 6- to 8-year-old patients (2928 ng•h/mL) and for the 10-mg FTC in 9- to 14-year-old patients weighing > 45 kg (3528 ng•h/mL).21
Potential dissolution differences between an oral granule formulation and the FCT could alter the rate of absorption of montelukast. The earlier tmax observed in the pediatric population receiving the oral granules compared to adults receiving the FCT is consistent with pharmacokinetic data from the CT formulation administered to adults,21 which is pharmaceutically similar to the oral granules. This would be clinically unimportant in pediatric patients since montelukast would be administered chronically, and its beneficial pharmacologic effects appear to be dependent on the extent of systemic exposure rather than peak plasma concentrations. It is interesting to note that in 2- to 5-year-old patients, the population Cmax estimate was also greater for the 4-mg CT compared with historical adult 10-mg FCT,20 demonstrating the effect of formulation on the kinetics of drug absorption. Despite the differences in Cmax, a formulation-associated difference in overall montelukast exposure (reflected by AUCpop) was not evident and, therefore, an impact on the efficacy and/or safety profile would not be expected. This assertion is supported, in part, by the demonstration of tolerability to montelukast in adults at Cmax values up to 19.5 µg/mL28—values more than 30 times those observed in the current study.
As recently reviewed by Muijsers and Noble,29 montelukast is a substrate for both CYP3A4 and CYP2C9 (P450 cytochromes) with in vivo and in vitro evidence of similarity in the rate of biotransformation between children 6 to 11 years of age and adults. Previous pharmacokinetic data for other pharmacologic substrates of these two CYP enzymes suggest the potential for increased rates of intrinsic clearance in older infants and young children compared with older children and adults.30 Assuming an average body weight of 70 kg for normal healthy adult subjects and 10 kg for this current population of infants (Table I), population CL/F values (Table IV) normalized for weight yielded parameter estimates of approximately 0.92 mL/min/kg and 2.1 mL/min/kg, respectively, for the adult and pediatric population, thereby suggesting a slightly increased clearance of montelukast in young infants. However, comparison of the elimination t1/2 values revealed average values for the pediatric patients in the current study that were only slightly shorter (30 min) in the infants compared to historical data in adults (Table V). In addition, the value for CL/F was similar to that previously determined following administration of a 4-mg CT dose in children 2 to 5 years of age.20 Comparability of the C24 h and AUCpop values between these populations would also suggest that any apparent age-associated differences in the elimination of montelukast would not adversely influence the exposure-response relationship of the 4-mg dose in infants and young children.
Montelukast was generally well tolerated, with a favorable safety profile in patients 6 to < 24 months old. The single dose of montelukast administered to pediatric patients in this study had few adverse events attributable to montelukast. Safety and tolerability of montelukast have been demonstrated in adults in doses up to 800 mg28 and at doses of 200 mg for 22 weeks.31 Montelukast has a safety profile similar to placebo in asthmatic patients 2 to 5 years old,8 6 to 14 years old,7 and adults.6 There were three cases of diarrhea and two cases of somnolence possibly associated with montelukast in this study. In a recent 6-week study of montelukast 4-mg oral granules in infants 6 to < 24 months of age, diarrhea occurred in 10.9% of patients on active compound compared to 12.3% of patients receiving placebo.32 Similarly, in a 12-week study of montelukast in 2- to 5-year-old children with asthma, the incidence of diarrhea was 8% and 10% in the montelukast and placebo groups, respectively, and somnolence was not a common clinical adverse experience.8 Accordingly, these data would support the apparent absence of an age association with respect to the adverse event profile for montelukast.
In conclusion, this study determined that a single 4-mg dose of montelukast oral granules given to patients 6 to < 24 months of age provided systemic exposure (AUCpop) similar to that of the clinically effective 10-mg FCT in adults. Thus, based on previous exposure-response data for montelukast, pharmacokinetic evidence supports the selection of the 4-mg dose in 6- to < 24-month-old asthmatic patients.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Support by a grant from Merck Research Laboratories, Rahway, New Jersey. Dr. Migoya, Dr. Hartford, Dr. van Adelsberg, Dr. Tozzi, Dr. Knorr, Dr. Deutsch, and Mr. Zhao are employed by Merck Research Laboratories; Dr. Kearns was an investigator in this study and received compensation from Merck Research Laboratories.
Submitted for publication August 27, 2003; Revised version accepted February 15, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, and observed C24 h for Montelukast after Administration of a Single 4-mg Dose of the Oral Granules to Pediatric Patients and of a 10-mg Film-Coated Tablet in Adults