Abstract
This study was designed to assess and compare the pharmacokinetics and tolerability of almotriptan, a 5-HT1B/1D agonist used to treat migraine attacks, in adolescents and adults. Healthy adolescents (n = 18) and adults (n = 18) received a single 12.5-mg dose of almotriptan after fasting overnight. Plasma and urinary almotriptan concentrations were measured by high-performance liquid chromatography. Pharmacokinetic parameters of almotriptan were determined by non-compartment analysis. The 90% confidence interval (CI) approach was employed to assess age effects. Mean Cmax, t max, area under the curve (AUC 0-∞), half-life, and percentage excreted in urine were nearly identical for the two populations. Mean oral (CLPO) and renal (CLR) clearances were similar between the age groups; however, weight-corrected CLPO was approximately 32% higher (90% CI 16, 51) in adolescents compared with adults. The higher weight-corrected CLPO appeared to offset increases in exposure expected on the basis of lower body weight in adolescents. The findings were the same when a subgroup (n = 9) of 12-14-year old children was compared with adults. The type, incidence and severity of adverse events were similar between the two age groups and were consistent with those reported previously during adult clinical trials. Based on these pharmacokinetic and tolerability findings, no dose adjustment for almotriptan would be required when treating patients as young as 12 years old.
Introduction
Migraine is an important illness among school-age children, with an incidence of about 5% of children (1). Every year this affliction causes the countless loss of school days and these children also must cope with the apprehension of developing a migraine, learning to avoid possible triggers, and accepting the likelihood of a lifetime of migraine. Therefore, there is an obvious need for effective and well-tolerated migraine treatment in adolescents.
Serotonin, 5-HT, is thought to be an intermediary in the pathogenesis of migraine (2). Almotriptan is a 5-HT1B/1D receptor agonist which is indicated for the acute treatment of migraine in adults. The drug is a selective ligand for the 5-HT1B/1D receptor, exhibiting an affinity 70 times greater for this receptor than for the 5HT1A receptors and showing negligible affinity for 5HT2 and 5HT4 receptors (3). Almotriptan is well absorbed orally, with an absolute bioavailability of approximately 70%. The drug shows dose-linear pharmacokinetics and a mean elimination half-life of between 3 and 4 h (4, 5). In humans, approximately 40–50% of the almotriptan dose is eliminated unchanged in the urine and appears to occur via active tubular secretion of the kidney (5). The balance of the dose is primarily metabolized, with < 5% excreted unchanged in the faeces. In vitro studies suggest that monoamine oxidase (MAO-A), cytochrome P-450 (CYP3A4 and CYP2D6) and flavin monooxygenase are responsible for almotriptan metabolism in man (6). Moclobemide, a MAO-A inhibitor, reduced almotriptan clearance by 27% (7), and verapamil reduced almotriptan clearance by 17% (8). These results suggested that MAO-A is responsible for the majority of almotriptan metabolism in man, with CYP3A4 making a lesser contribution.
In this study, plasma and urine drug concentrations were measured to assess the pharmacokinetics of almotriptan in adolescents. This pharmacokinetic evaluation was performed to support dose selection for future efficacy studies in this population.
Subjects and methods
This study was conducted at North-west Kinetics (Tacoma, WA, USA) and was approved by the institutional review board (Quorum Review, Inc., Seattle, WA, USA). The study was conducted in accordance to the Declaration of Helsinki and the principles of good clinical practice.
Subjects
Subjects were healthy male and female adolescents (12–17 years of age) and adults (18–55 years of age), with or without a history of migraine. Adolescents were required to have a body mass index (BMI) within the 5–95 percentile for their age and sex as defined by the Unites States National Center for Health Statistics (9). Adults were required to have a BMI of 18–29 kg/m2. All females had a negative serum pregnancy test prior to entry into the study.
Study design
The study was at a single centre, and utilized an open-label, parallel group design. Thirty-six subjects (18/group) were enrolled. Subjects were administered a single oral 12.5-mg dose of almotriptan with 240 ml of room temperature water after an overnight fast (approximately 10 h). Urine collections and serial blood samples were then taken over a 24-h period for the pharmacokinetic assessment.
Clinical assessments
Subjects were monitored throughout the treatment period for the occurrence of adverse events, defined as any untoward medical occurrence, regardless of its relationship to study medication. Safety was assessed by vital signs, ECGs and routine laboratory tests.
Plasma and urine almotriptan analysis
Venous blood samples of 3 ml each were collected into sodium heparin tubes from each volunteer prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 h after dosing. Plasma was prepared and transferred to polyallomer sample tubes and frozen at − 20 °C or lower until assay.
Plasma samples were assayed for almotriptan concentrations using a validated, sensitive, and specific LC/MS/MS assay (7). The lower limit of quantification (LLOQ) for almotriptan was 0.500 ng/ml. Assay precision, expressed as the coefficients of variation (CV) of the estimated concentrations of quality control standards, was 9.9%, 4.8%, and 5.2%, respectively, for the 1.5, 50, and 150-ng/ml QC pools.
Urine was collected predose and at 0–4, 4–8, 8–12, and 12–24 h after the dose. A 20-ml aliquot of each collection interval was removed and frozen at or below − 20 °C until assayed for almotriptan.
Urine samples were assayed for almotriptan concentrations using a validated, sensitive, and specific LC/MS/MS assay (7). The LLOQ for almotriptan was 50.0 ng/ml. Assay precision, expressed as the CV of the estimated concentrations of QC samples, was 3.1%, 2.6%, and 2.5%, respectively, for the low (150 ng/ml), medium (2500 ng/ml), and high (7500 ng/ml) QC pools. The mean assay accuracy was 100.2%, 99.2%, and 100.5%, respectively, for the low, medium, and high QC pools.
Data analysis
Standard non-compartmental methods using Kinetica 2000, version 3.1 (InnaPhase Corp., Philadelphia, PA, USA), were employed to estimate pharmacokinetic parameters. C max and t max were the observed maximum plasma concentration and the time at which it occurred, respectively. The terminal elimination rate constant (λz) was determined by linear regression of the terminal portion of the log concentration–time profile. The terminal half-life (t 1/2) was calculated as 0.693/λz. Area under the plasma concentration–time curve (AUC0–∞) was determined by trapezoidal rule up to the last time at which a measurable concentration was observed and extrapolated to infinity. Oral clearance (CLPO) and renal (CLR) clearances were computed by non-compartmental methods according to the following relationships: CLPO = D/AUC0–∞ and CLR = Ae (t)/AUC0–t where D is the administered dose, Ae the amount of drug excreted in urine to time t. Due to incomplete urine collections made in a number of adolescent subjects during the 8–24-h postdose period, CLR was calculated based on 0–8-h urinary excretion data. The percentage of dose excreted unchanged in urine (Fe%) was calculated based on the mass of unchanged drug excreted in urine during the 0–24-h period where data were available.
Differences between groups in pharmacokinetic parameters were assessed by the 90% confidence interval (CI) approach using natural log-transformed data. All statistical analysis were performed using the SAS statistical analysis package (SAS, Cary, NC, USA) (10). The study was powered to detect a 20% difference in AUC0–∞ at an α level of 0.05.
Results
Demographics
Thirty-six healthy subjects were enrolled in this study, 18 adolescents and 18 adults. All 36 subjects completed the study. Of the 18 adolescent subjects who enrolled in this study, nine were male and nine were female. Ten subjects were Caucasian, four were black and four were not listed. The mean age of subjects was 14.9 years (range 12–17 years) and weight was 62 kg (range 36–90 kg). The adolescent group was equally distributed (n = 9 each) between the ages of 12–14 and 15–17 years. Of the 18 adult subjects enrolled in this study, nine were male and nine were female. Fourteen subjects were Caucasian, one was black, one was Asian, and two were not listed. The mean age of subjects was 37.0 years (range 18–53 years) and weight was 74 kg (range 53–94 kg). Two adolescents and three adults had a history of migraine.
Pharmacokinetics
The mean plasma almotriptan concentrations following administration of a 12.5-mg dose of almotriptan to adolescents and adults are shown in Fig. 1. From the concentration vs. time plot, it is clear that appreciable overlap in the plasma concentrations at the individual time points exists among the two age groups. Mean almotriptan pharmacokinetic parameters as well as the ratio of the population geometric means and 90% CIs are summarized in Table 1. AUC0–∞, C max, t max, t 1/2 and non-corrected oral clearance were similar for the two age groups, with ≤ 11% difference between adolescents and adults. However, mean body weight-corrected oral clearance in children was 32% higher relative to adults (90% CI 16, 51). Individual concentration–time data are shown in Fig. 2, which depicts the range of plasma concentrations occurring in the two age groups. The C max of two of the 18 adolescents exceeded the upper range of adults in this study, but only by 1.6-fold or less. The adolescent showing the highest C max was a 12-year-old male weighing 36 kg, while the other was a 14-year-old female weighing 59 kg. Thus, one adolescent was of lowest weight while the other approximated the mean weight of this age group. In a separate analysis comparing adolescents of 12–14 years of age (n = 9, mean body weight of 58 kg) with adults (n = 18, with mean body weight of 74 kg), no statistically significant (P < 0.05) difference with the exception of mean weight-corrected oral clearance was detected. Corrected oral clearance was higher in the 12–14 age group (0.689 ± 0.134 ml/min per kg) compared with adults (0.518 ± 0.144 ml/min per kg).
Mean (± SD) plasma concentrations of almotriptan following the administration of 12.5 mg almotriptan to adolescents and adults.
Individual plasma concentrations of almotriptan following the administration of 12.5 mg almotriptan to adolescents (upper panel) and adults (lower panel). The stippled lines are subjects with a history of migraine.
Mean (± SD) pharmacokinetic parameters for almotriptan following oral administration of 12.5 mg to adolescents and adults
∗Geometric mean with 90% confidence interval relative to adults.
†N = 17.
‡N = 9, 0–24 h cumulative excretion.
Clinical
Few adverse events were reported during the course of the study. All events were non-serious and mild to moderate in intensity. Of the eight subjects in whom an adverse event was reported, three were adolescents and five were adults. The investigator attributed only one of the events (dry mouth) as being possibly related to study medication. No clinically significant drug-related abnormal laboratory test results, vital signs or ECGs were observed.
Discussion
Although many factors contribute to drug disposition, children of adolescent age are of lower body weight on average than their adult counterpart and thus administering an adult dose to a child may result in higher systemic drug exposure. The current study was conducted in order to evaluate this potential outcome and provide guidance on almotriptan dosing in future trials in adolescents. For direct comparison of the data, the study was conducted in parallel with an adult cohort. Healthy subjects with or without a history of migraine were permitted to participate since the pharmacokinetics of triptan agents are similar between healthy subjects and subjects with a history of migraine outside of an attack (11). The only effects observed on the pharmacokinetics have been a delayed time to peak concentration during the migraine, and these were generally modest and appeared drug specific (11). The presence of migraine has been shown not to delay the absorption of almotriptan in adults (12), thus the study was conducted without regard to a migraine attack.
Although adolescents were of lower body weight, no statistically significant differences were observed in measures of almotriptan exposure, i.e. AUC0–∞ and C max, between the two age groups. The C max of two of the 18 adolescents did exceed the upper range of adults but only by 1.6-fold or less. The magnitude of this difference would not elicit a dose adjustment for these individuals considering the safety margin of this drug. A higher rate of weight-corrected clearance was observed in adolescents compared with adults, which appeared to offset increases in exposure expected on the basis of lower body weight in adolescents. The findings were the same when a subgroup of 12–14-year-old children was compared with adults. This observation was not unexpected, since many drugs exhibit a higher systemic clearance in children than in adults, especially when normalized to body weight (13). These results are also consistent with those reported from a study in which a single dose of zolmitriptan was given to adolescents and to adults (14). Similar zolmitriptan AUC0–∞ and C max were observed for the two age groups, and adolescents appeared to exhibit a higher rate of elimination than that of adults.
Almotriptan given as a single 12.5-mg dose was well tolerated. Based on the findings of this study, no dose adjustment for almotriptan would be required when treating patients as young as 12 years old.