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PEDIATRICS |
From the Departments of Pharmacy and Pediatrics, Pediatric Pharmacology Research Unit, and Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee Health Science Center, Memphis (Dr. Christensen, Dr. Mottern); Pediatric Neurology, Inc., South Bend, Indiana (Dr. Jabbour); LeBonheur Children's Medical Center, Memphis, Tennessee (Dr. Christensen, Dr. Mottern, Dr. Jabbour); and EMF Consulting, Aix-en-Provence, France (Dr. Fuseau).
Address for reprints: Michael L. Christensen, PharmD, University of Tennessee Health Science Center, LeBonheur Children's Medical Center, 777 Washington Avenue, Room P420, Memphis, TN 38103.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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25 kg received 5 mg (n = 3), children ages 6 to 8 years weighing > 25 kg and children ages 9 to 11 years of age weighing 40 kg received 10 mg (n = 10), and children ages 9 to 11 years weighing > 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng•h/mL (9.7-79.8), 42.4 ng•h/mL (30.6-58.8), and 49.2 ng•h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (Cmax) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.
Key Words: Pharmacokinetics • sumatriptan • pediatrics • migraine
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The study was performed in accordance with the principles of good clinical practice. The University of Tennessee's institutional review board approved the study protocol and informed consent. Parents or legal guardians gave written informed consent, and subjects gave written assent.
Study Design
This was an open-label, uncontrolled, single-dose, single-center study in children with a history of migraine to determine the pharmacokinetics, safety, and tolerability of doses of 5, 10, or 20 mg sumatriptan nasal spray administered outside a migraine attack. The sumatriptan dose was sprayed up one nostril only. The sumatriptan nasal spray preparation contained 5, 10, or 20 mg in a 100-µL unit dose of aqueous buffered solution. The dose of sumatriptan nasal spray was determined based on a weight distribution in specified age ranges to achieve a similar exposure to adults and adolescents treated with 20 mg sumatriptan nasal spray (Table I). Children 6 to 8 years of age weighing less than or equal to 25 kg received 5 mg, and children weighing more than 25 kg received 10 mg. Children ages 9 to 11 years weighing less than or equal to 40 kg received 10 mg, and children more than 40 kg received 20 mg. Subjects were instructed to sit down, blow their nose to clear the nasal passages, keep their head in an upright position, close their left nasal passage, administer the nasal spray into the right nasal passage, and keep their head level for 10 seconds, breathing in through the nostrils and out through the mouth. The subjects were provided a light breakfast prior to dosing, free access to fluids, and lunch approximately 4 hours after dosing. The subjects remained in the clinical research unit for the entire time of the pharmacokinetic sample collection.
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Data from another pediatric study of sumatriptan nasal spray12 were used for a combined population pharmacokinetic analysis: adolescent migraineurs were treated in an open, uncontrolled, single-dose study to determine the pharmacokinetics, safety, and tolerability of 20 mg sumatriptan nasal spray administered outside of an attack. Twenty-one male and female subjects (age 12-17 years, weight 45-78.6 kg, height 140-177 cm) were treated. Study procedures, bioanalytical methods, and data analysis were similar to those used in the children. Noncompartmental pharmacokinetic (PK) parameters were determined from 16 subjects; population PK parameters were determined from 21 subjects. Noncompartmental pharmacokinetic parameters in adolescents were not significantly different from adults. Population analysis showed that the clearance and volume of distribution increase slightly with age and body size.
Analytical Methods
Plasma sumatriptan concentrations were determined using a new liquid chromatography with a tandem mass-spectrometric detection method, validated over the calibration range 0.1 to 20 ng/mL for a plasma volume of 0.4 mL.13 Internal standard was sumatriptan. Accuracy and precision were calculated using interpolated concentrations of quality control samples at three concentration levels. The bias (accuracy) was 5.8%, and the precision was 13.7% coefficient of variation (CV).
Pharmacokinetic and Statistical Analyses
Venous blood samples (2.5 mL) for the measurement of plasma sumatriptan concentrations were obtained before dosing and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, and 8 hours after administration of the dose. After the blood sample collection, the sample was centrifuged at 4°C at 1500g for 10 minutes and the plasma separated. The plasma samples were placed in labeled polypropylene tubes and stored frozen at -20°C until analysis. The pharmacokinetic parameters were calculated with noncompartmental analysis. The observed maximum plasma concentration (Cmax) and the time (tmax) to reach Cmax were derived from the measured values. The linear terminal elimination rate constant (
z) of the log concentration of sumatriptan versus time was calculated by the least squares method. The elimination half-life (t1/2) was calculated as 0.693/z. The AUC was calculated as linear in the ascending portion of the concentration-time curve and log-linear in the descending portion of that curve. Predose BQL values were set to zero for median plots and areas calculation.
The analysis of PK parameters comprised summary statistics for Cmax, AUClast, AUC
, and t1/2: arithmetic mean and standard deviation; median, minimum, and maximum; geometric mean; and 95% confidence interval. tmax was summarized using arithmetic mean, standard deviation, and median, minimum, and maximum. Where pharmacokinetic data were occasionally missing, data were summarized using all available data.
To better define the relationships between age, body size, and exposure and describe precisely the early absorption phase of sumatriptan, a population pharmacokinetic model was fitted to the data. The population pharmacokinetic modeling involved two steps; the first included only children data (current study), and the second used pooled data from the children and adolescent studies.12 The analysis used the NONMEM software.14 A two-process absorption model previously developed to model adult and adolescent sumatriptan data15-17 was used to describe the observed double peak (presented later in Figure 4). A fraction of the dose administered was absorbed by a first-order process from the depot. The remaining fraction was absorbed, after a lag time, by a zero-order process. The systemic bioavailability was not estimated from this data set. A one-compartment model described the disposition. The population parameters estimated are the fraction of the dose absorbed by the first (F1) and the second absorption (1-F1) processes, the rate constant of absorption (Ka), the duration of the zero-order absorption and the lag time (D2 and ALAG2), the apparent clearance (CL/F), and the apparent volume of distribution (Vd/F). The methods selected for minimization were the first-order (child data) and first-order conditional estimation (child and adolescent pooled data) methods. All error models to describe between-subject variability were exponential models. The residual error was modeled as proportional to the predictions. Diagnostics used goodness-of-fit plots of weighted residuals and population or individual predictions versus predictions, observations, and time. Individual predictions were used to ascertain the model in fitting the individual profiles. The effects of body size and age were evaluated after initial selection by univariate analysis; selected covariates were included in the model simultaneously, and the final model was determined after backward elimination (p < 0.001). The choice of body size parameters (weight, height, body surface area, or lean body mass) and age on CL/F and Vd/F was guided by prior knowledge of the pharmacokinetics of sumatriptan in adults and adolescents. The selection of one of these heavily correlated covariates used the likelihood ratio test, based on the change of the objective function. Body weight was the best predictor of clearance; however, age (or height) was consistently a better predictor of Vd than weight in this population, which included bigger children or adolescents.
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Safety Assessments
Adverse event data were obtained from information volunteered by subjects as well as by monitoring subjects by the study staff. Measurements of vital signs (heart rate, blood pressure, and respiratory rate) were performed at screening; prior to dosing and at 0.5, 1, 2, 4, and 8 hours after dosing; and at a follow-up visit that occurred 2 to 10 days after dosing. A physical examination was performed at screening, prior to drug administration, and at the follow-up visit; clinical laboratory tests were performed at screening and at the follow-up visit. A 12-lead electrocardiogram was obtained at screening, prior to dosing, after the 8-hour blood sample, and at the follow-up visit.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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No serious adverse event occurred after drug administration: 15 of 17 subjects reported bad taste, 3 had a nosebleed or itching, and 1 reported locking of jaw with pain while eating. None of these events led to study withdrawal, and all events resolved.
The individual (Figure 1) and median (Figure 2) concentration-time profiles of sumatriptan nasal spray 5, 10, and 20 mg are depicted. Figure 3 shows that concentrations in children are comparable to those in adolescents and that both children and adolescent profiles seem to indicate a slower absorption than in adults.12,16,18 Individual profiles show that the initial peak of absorption is less pronounced in the younger population than in adults. The noncompartmental pharmacokinetic parameters are summarized in Table II, comparing child data to adolescent and adult data. The confidence intervals across doses indicate that the dose selection based on age and body weight performed reasonably well in providing comparable Cmax. However, Cmax and AUC observed in the younger age group (3 children treated with 5 mg) appear more variable and lower than in the other age/dose groups. It will be important to evaluate the pharmacokinetic disposition of intranasal sumatriptan in additional subjects weighing less than 25 kg before dosing recommendations can be made. The half-life estimated was slightly less in the younger age group, with 1.4 versus 1.7 hours for adolescents and adults.
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Doses of 5, 10, and 20 mg sumatriptan nasal spray are available for treatment of migraine in adults. In adults,16 body size parameters were the only factors affecting sumatriptan PK parameters. The analysis of pooled pediatric data from children 6 to 17 years of age was undertaken purely to better define the relationship between sumatriptan PK and children demographic variables (age and body size), providing a rationale for initial dose selection based on age and body size rather than age only. The analysis of the current study data was conducted in two steps: the model identified in the adolescent study12 was fitted to children data (17 children, 153 concentration-time data) without further development. Pooled data analysis was then conducted on the pediatric population data from both studies (38 subjects, 305 concentration-time data). The structural PK model is represented in Figure 4. Since the slope of the relationship between clearance and weight was increased in children compared to adolescents, a new model for clearance was developed. This model used a second-order polynomial function to describe the relationship between clearance and body weight. The population apparent clearance is given by the following equation:
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The shape of the relationship between age and volume of distribution was not modified. The volume of distribution is given by the following equation:
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The results of the estimation in the pooled pediatric population are presented in Table III. The first term of the population apparent clearance (CL/F) was 215 L/h for a subject with a normalized weight of 1 (weight/30 kg), and the effect of weight was reduced by a factor of 17.9 L/h for increasing weight as a function of the normalized weight to the power 2: the clearance predicted for a subject weighing 30 kg was 197 L/h. Between-subject variability on CL was 28% CV. The volume of distribution was 751 L for a child age 11 years, with a CV of 43%. The initial absorption was very rapid in all subjects, with a Ka of 7 h-1. A second absorption process started 0.4 hours (with 98% CV between subjects) after administration and lasted 1.3 hours. The fraction of the dose absorbed through this initial absorption process was 33.3% of the total amount absorbed, with variability between subjects of 45%. This fraction of the dose initially absorbed appears to be lower in children than in adolescents and in adults, which could be related to a different anatomy of the face and nose in younger children. The residual error was moderate, at 24%. Figure 5 illustrates the large subject variability in exposure, resulting from variability in absorption and in disposition parameters as well as variability in the dosing regimen, which was selected from the three unit doses: 5, 10, and 20 mg. Model predictions for each subject, using individual parameter estimates from the final model, were obtained using posterior estimation. No other structural PK model was evaluated. Goodness-of-fit plots (Figure 6) show no bias and good adjustment to individual data.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Sumatriptan nasal spray was rapidly absorbed, achieving a maximal concentration within 2 hours of administration. The noncompartmental pharmacokinetic parameters of sumatriptan nasal spray from children were similar to the parameters observed in adolescents and adults.12,23 The degree of variability in the pharmacokinetic parameters observed in this study and in the adolescent study was also seen in adult pharmacokinetic studies. There was an effect of body size on the apparent clearance, and volume of distribution increases with age. The absorption appears to be slower in the younger age group, as shown by Figure 3 and by a smaller fraction absorbed by the initial, fast, first-order process. The bioavailability of nasal spray in adults was 15% relative to the subcutaneous formulation,18 resulting from a metabolic first-pass effect related to the MAO enzymes. It is believed that a fraction of a nasal dose is absorbed initially through the nasal mucosa, while the remaining is swallowed and absorbed through the gastrointestinal tract. In adults, sumatriptan pharmacokinetic data have been collected after oral and nasal administration in healthy subjects and in migraineurs during an attack: the absorption from an oral tablet was delayed during a migraine attack due to gastric stasis, nausea, and vomiting.24 However, disposition parameters were not affected. The nasal administration offers an advantage over the tablet administration since it provides faster absorption immediately after dosing, resulting in faster initial relief of migraine symptoms.
The age and weight dose adjustment scheme used in the current study was successful in providing no greater systemic exposure than observed in adults and adolescents treated with 20 mg sumatriptan nasal spray. However, since plasma concentrations during the absorption phase seem to determine the efficacy in treating a migraine attack, it is unknown whether the administration of nasal spray to young children would provide therapeutic concentrations during the 2 hours postdose.
Migraine is an important clinical problem in school-age children. Mortimer et al2 found that about 5% of children who suffer from headaches have migraines and is in the range of the 2.7% to 10% reported by others.1-6 Of those with migraines, the age of onset was 4 years for 26% of the children, and 98% had their onset by 9 years of age. The most common treatments have included the analgesics, ergotamine, and a medication to control nausea and vomiting. For approximately 50% of patients with mild to moderate migraine pain, a mild analgesic is effective.16 Ergotamine use is often limited by side effects.8,25 Although other agents are used to abort migraines (e.g., ergotamine compounds and the 5-HT1 selective agonists), none are approved for use in children. The most effective therapies for migraine are those that can be given quickly at the beginning of the attack and have a rapid onset of action. Oral therapies are often not effective in children because of gastrointestinal symptoms, nausea, and vomiting. Children may also want to avoid the use of injectable drugs. The intranasal route offers a possible route of administration when oral or parenteral routes may not be desirable. One concern in younger children is whether they can successfully administer a dose of intranasal sumatriptan. The results from the children study would indicate that their technique was adequate and had dose-adjusted systemic exposures that were similar to those of adolescents and adults.
Sumatriptan nasal spray has been shown to be effective in the treatment of adults and adolescents with migraine. There is only limited experience of the effectiveness in children. In a study of 14 children with a history of a least two migraines per month, patients were randomly assigned in a crossover approach to sumatriptan or placebo treatment for two subsequent migraines.26 Sumatriptan was found to be more effective than placebo. After sumatriptan, 12 of 14 subjects reported a decrease in pain intensity compared to 6 of 14 subjects after placebo, and 9 of 14 subjects following sumatriptan reported complete migraine relief compared to only 2 of 14 subjects after placebo. Migraine-associated symptoms were also significantly reduced after migraine. An uncontrolled study of either 5 or 20 mg of sumatriptan nasal spray in 10 patients 5 to 12 years of age suggested effective headache relief.27 Appropriately designed clinical trials will be necessary to establish the effectiveness and tolerability of sumatriptan nasal spray in children younger than 12 years of age. These studies should also further determine the optimal dose in younger children.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication July 7, 2003; Revised version accepted January 18, 2004.
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REFERENCES |
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