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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Elkind Headache Center, Mount Vernon, New York (Dr Elkind, Dr Ishkanian) and Vernalis Ltd, Wokingham, Berkshire, United Kingdom (Dr Wade).
Address for reprints: Arthur H. Elkind, MD, Elkind Headache Center, 12 North 7th Avenue, Mount Vernon, NY 10550.
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ABSTRACT |
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 TOP ABSTRACT STUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Frovatriptan • adolescents • pharmacokinetics • migraine
Overall, migraine symptoms in adolescents are comparable to those seen in adults7; however, there are some differences. Migraine pain episodes are generally shorter in adolescents than adults (1-48 hours vs 4-72 hours in adults), and pain is bilateral, frontal/temporal, and pulsatile more commonly in adolescents than in adults. Adolescent migraineurs also appear to have an increased frequency of associated symptoms—including vomiting, nausea, photophobia, and phonophobia—compared with adults.7,8 Interestingly, results from a meta-analysis of nearly 2000 adolescent subjects who participated in various trials of triptan therapy indicate an increased incidence of headache on Monday, Tuesday, and Wednesday compared with the weekend, and headache was more prominent during daytime hours (6:00 AM to 6:00 PM).4
Traditionally, migraine therapy for adolescents has emphasized over-the-counter medications, the adoption of improved lifestyle habits (eg, good sleep hygiene and balanced diet), and avoidance of triggers such as stress, caffeine, and intense physical activity. The efficacy and tolerability of the triptans in treating migraine in adolescents have recently been reviewed.7 In the clinical studies, an elevated placebo response was noted that negatively affected treatment evaluation7; nevertheless, adolescents clearly benefit from triptan therapy. However, no specific migraine medications have been approved in the United States for acute treatment of migraine in adolescents,7 and only the sumatriptan nasal spray is approved for use in adolescents in the United Kingdom.
Frovatriptan is a selective 5-HT1B/1D receptor agonist that is available for acute treatment of migraine with or without aura in adults. In the triptans class, frovatriptan is noteworthy for its long elimination half-life (
26 hours) and strong 5-HT1B receptor potency,9,10 both of which may be associated with a reduced probability of migraine recurrence.11 Frovatriptan has a wide therapeutic window, with dose-ranging studies indicating good tolerability throughout the dose range tested (0.5-40 mg).12 The risk of drug interactions is low, and frovatriptan has been demonstrated to have no clinically significant interactions with other medications commonly administered to patients with migraine.13
The goal of the current study was to determine the key pharmacokinetic (PK) parameters of frovatriptan in an adolescent population and to compare the results with a comparable study in adults to assess whether dosing adjustments are a concern when frovatriptan is used in adolescents.
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STUDY DESIGN AND STUDY SUBJECTS |
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TOPABSTRACTSTUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects were eligible to participate if they met the following inclusion criteria: male or female between 12 and 17 years of age with a diagnosis of migraine, as determined by International Headache Society criteria (IHS Headache Classification Committee, 1988); at least a 6-month documented history of experiencing migraine episodes; and freedom from migraine symptoms in the 24 hours before treatment with study medication. Female subjects of childbearing potential were required to have a negative pregnancy test, and sexually active subjects were required to use adequate methods of contraception. Subjects were excluded from participation if any of the following criteria were met:
Study Procedures
The study included screening, dosing/sampling (day 1), and follow-up (day 7 ± 1) visits. Subjects were admitted to the unit on the morning of the day of dosing after fasting from 10 PM the previous night. Study medication was administered orally to subjects in a fasting state. Blood samples (8 mL into heparinized tubes) were taken at predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 48 hours postdose. Urine was collected over the following time intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours postdose. After PK sampling at 2 hours postdose, the subjects were offered a standardized low-fat breakfast, and at 5 hours postdose, a standardized low-fat lunch was offered. Subjects were allowed to leave the clinic after the 8-hour sampling; they returned to the clinic for the remaining assessments.
Adverse events were monitored throughout the study at each of the PK sampling time points and at the follow-up visit on day 7. A full physical examination was performed at the screening and follow-up visits, and an abbreviated examination was performed just before dosing. Vital signs (diastolic and systolic blood pressure, pulse rate, and oral body temperature) were recorded at each clinic visit and each PK sampling time point. A 12-lead electrocardiogram (ECG) was obtained after 5 minutes' supine rest at the screening visit, predose, 4 and 24 hours postdose, and at the follow-up visit. Clinical laboratory tests for routine biochemistry and hematology assessments were performed at the screening visit, predose, and 8 hours postdose. Urinary pregnancy testing for female patients was performed before dosing.
Subjects refrained from vigorous exercise for 7 days before dosing and during the study period until completion of the follow-up visit. Alcohol- and caffeine-containing food and beverages were not permitted from 48 hours before dosing until the last PK sample was taken. Smoking was not permitted in the clinic. No medication was allowed during the study, except oral contraceptives and occasional paracetamol (acetaminophen); concomitant medication was reviewed at each visit and recorded.
Analytical Methods
Frovatriptan concentrations in whole blood were determined by liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantitation (LLOQ) of frovatriptan in whole blood was 200 pg/mL. The interassay precision of quality control samples analyzed throughout the study was 8.1% at 750 pg/mL, 12.9% at 7500 pg/mL, and 15.6% at 16,000 pg/mL. Interassay accuracy varied between 82.8% and 98.2%.
Urine samples were prepared by dilution with an ammonium acetate (10 mM, pH 4.0)/acetonitrile solution (87:13 v/v). The resulting solutions were analyzed for frovatriptan by liquid chromatography with tandem mass-spectrometric analysis. In urine, the LLOQ was 50 ng/mL. The interassay precision of quality control samples analyzed throughout the study was 10.8% at 150 ng/mL, 16.4% at 750 ng/mL, and 10.6% at 2500 ng/mL. Interassay accuracy varied between 98.3% and 105.9%.
PK and Statistical Analyses
The PK parameters were determined from the whole blood and urine concentrations of frovatriptan using noncompartmental procedures. The parameters determined the following:
), that is due to extrapolation from tz to infinity (%AUCex), 
z),
In addition, AUC0-24h, AUC0-tz, AUC0-, and Cmax were normalized (norm) to a dose of 1 mg and a body weight of 70 kg (dividing by the dose level of frovatriptan and multiplying by the subject's weight, after conversion to kg, and dividing by 70).
The PK analyses were performed for the adolescent subject participants and also for male and female adult subjects (nonmigraineurs) from a previous study14 that was selected because it had a very comprehensive PK sampling regime and provided the best comparative data. The adult study contained more data points than was felt ethically possible to use in an adolescent population, so to ensure the validity of the analysis with the adult population from the prior study, the adult PK data were recalculated using equivalent sampling time points and comparable data analyses to those used in the current adolescent study.
The sample size was based on practical and ethical considerations rather than statistical concerns. This was a pilot study that sought to minimize the exposure risk for first-time use in adolescents while obtaining a reasonable preliminary data set. Summary statistical analyses were performed for the total population, and separate summary statistics were computed for each gender and each age and gender subgroup. Mean differences between the groups were calculated, and the residual variance from the ANOVA was used to calculate 95% confidence intervals (CI) for the difference. These values were back-transformed to give a point estimate and a 95% CI for the ratio. Geometric least squares means, ratios, and 95% CIs were calculated for the age group and gender comparisons. All tests were 2-sided and used the 5% level of significance. Pairwise comparisons by age and gender were performed (female subjects ages 12-14 with female subjects ages 15-17, male subjects ages 12-14 with male subjects ages 15-17, female subjects ages 12-17 with adult female subjects and male subjects ages 12-17 with adult male subjects). Comparable gender comparisons in the same age categories (including adults) were also made (female subjects ages 12-14 with male subjects ages 12-14, etc). Safety and tolerability data were summarized and descriptive statistics applied where appropriate.
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RESULTS |
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TOPABSTRACTSTUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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PK Results
Geometric mean whole-blood concentrations of frovatriptan over time by gender in adults and the 2 age groups of adolescents are shown in Figure 1, and PK parameters in whole blood and urine are summarized in Table II. The whole-blood concentration versus time profiles were characterized by a moderately rapid absorption in all subjects, with the tmax occurring later in female adolescents than in males (4 hours postdose in females and 2 hours postdose in males). In adults, the median tmax was 2 hours for males and 3 hours for females. Following attainment of Cmax, whole-blood concentrations of frovatriptan appeared to decline in a biphasic manner, with the start of the apparent terminal elimination generally occurring between 4 and 16 hours postdose. The mean apparent t1/2 was similar for male (15-17 years) and female (12-14 and 15-17 years) subjects with values of 24.7, 25.5, and 20.7 hours, respectively. However, the mean t1/2 for male subjects 12 to 14 years was markedly shorter, with a mean of 12.2 hours and individual values ranging from 7.1 to 20.1 hours. In adults, the calculation of the t1/2 was complicated due to limited data but appeared to be similar in adult male and female subjects, with values ranging from 16.9 to 24.4 hours. Adult t1/2 values also appeared similar to those in 15-year-old to 17-year-old male and adolescent female subjects.
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In adolescents, AUC0-24h and Cmax were approximately 2-fold higher in female subjects compared with male subjects. Systemic exposure in male subjects was similar for both subpopulations but was approximately 1.5-fold higher in the 12- to 14-year-old female subjects compared with the 15- to 17-year-old female subjects. Similar results were seen in the adult population, with AUC0-24h and Cmax approximately 2- and 1.7-fold higher, respectively, in female subjects compared with male subjects. Comparison between the adult and combined adolescent data shows the AUC0-24h and Cmax to be slightly lower in both male and female adolescents by approximately 20% and 30%, respectively.
The PK parameters in urine are summarized in Table III. The fraction of dose excreted as unchanged frovatriptan was approximately 3-fold higher in female subjects (9%-10%) compared with male subjects (2%-4%) for both 12- to 14-year-old adolescents and adults. The renal excretion was lower (approximately 3% of the dose) in female subjects 15 to 17 years old, and the renal clearance in this group was approximately 50% lower than in the other female groups. Data were not available for male subjects 15 to 17 years old. Renal clearance was generally similar in adolescent subjects (12-14 years) and adults, being slightly higher in female subjects than in male subjects.
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Safety and Tolerability
There were no serious adverse events (AEs), treatment-related AEs, or withdrawals due to AEs during the study. A total of 10 AEs were reported during the study. Two of these were predose, and 2 were in placebo recipients. The remaining 6 treatment-emergent AEs were all of mild or moderate intensity. AEs included 2 instances of abdominal pain, 2 instances of diarrhea, and 1 episode each of vomiting, vasovagal attack, laceration, and head injury. The laceration and head injury were not drug related. There were no clinically significant changes in ECGs or vital sign readings taken from screening and during study drug administration. Likewise, there were no clinically significant changes between predose and postdose laboratory values. One 12- to 14-year-old male subject vomited approximately 1.5 hours after dosing and was not included in the statistical analyses.
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DISCUSSION |
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TOPABSTRACTSTUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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values for male subjects ages 12 to 14, which were approximately 46% and 53% lower, respectively, than for those male adolescents ages 15 to 17 years. Normalized AUC0-24h and normalized Cmax were statistically significantly lower (38% and 46%, respectively) for adolescent males compared with adult males. As previously observed in adults, gender differences were noted in adolescent subjects. All PK parameters were higher for female subjects compared with their male counterparts, and the differences were highly statistically significant despite wide CIs. Other studies in adults have shown that values of AUC and Cmax (but not t1/2) are consistently higher (up to 2-fold) in female subjects than in males.9 This difference has been attributed in part to a greater absolute bioavailability in female subjects (30%) compared with males (22%) and in part to a higher volume of distribution and clearance in males. These gender differences in exposure to frovatriptan have been shown to have no clinically significant effect on efficacy or safety, and no dosage adjustment is necessary. It should also be noted that even if there were a number of parameters that were statistically significant, it is unlikely that they would be considered clinically significant, as frovatriptan has an exceptionally wide therapeutic window.
There were limitations in the current study that should be noted: the number of participants in each gender/age subgroup was small (n = 5), and the number of time points in the 12- to 24-hour period was restricted, as the participants were not asked to spend the night in the clinic because of their young age. Because the comparator adult population data set was reduced to correspond exactly with the adolescent sampling regimen, the ability to determine the t1/2 in adolescents was compromised; thus, these data should be regarded as approximate. In general, as assessed from the geometric coefficient of variation, moderate to high inter-subject variability (up to 78.1%) was noted for AUC0-24h and Cmax for both male and female subjects.
Although direct contemporaneous comparison of data is most desirable, the study we used to indirectly compare the adolescent with the adult population was considered to be appropriate because the studies were of similar design, and all the parameters (other than reporting of AEs) were measured objectively. In addition, the analytical techniques and methods used were the same. However, there were some potentially important differences between the 2 studies: all adolescent subjects were African American, whereas the comparator adult population was composed entirely of Caucasian participants. Adolescent subjects in the current study had a history of migraines, whereas the comparator adults were nonmigraineurs. We do not believe these differences in the study populations are likely to have affected the results significantly, as there is no evidence suggesting that frovatriptan PK profiles differ based on race or migraine status. An interaction analysis of the frovatriptan database did not show any differences in efficacy or tolerability between African American and Caucasian patients. Hence, if there are differences in the PK pharmacokinetics, they are not clinically meaningful.
The female adolescents in both age groups were heavier and taller than their adult counterparts. This may have influenced the pharmacokinetics to some extent, and it could be expected that a small female young-adolescent might display slightly greater exposure to frovatriptan than that seen in the female adolescents in this study. Given that the blood levels in female adolescents in this study were 30% lower than in female adults, we do not think that a small increase in exposure (as might be anticipated in smaller female adolescents) will lead to any clinically meaningful effects.
The results of this study were consistent with other studies evaluating triptans in adolescents. PK studies evaluating both intranasal sumatriptan (20 mg)15 and oral naratriptan (2.5 mg tablet)16 in adolescents indicated that PK parameters were similar in adults and adolescents and further suggested that no dose adjustments are needed in treating adolescents.
The PK studies of frovatriptan have also been evaluated in other special populations.9 In healthy elderly adults, ages 65 to 77 years, mean blood concentrations of frovatriptan were higher in elderly subjects compared with younger adults. This may have been due to weight differences and/or age-associated changes in metabolism (especially hepatic and renal), intestinal motility, or other functions. Regardless of the changes in PK parameters, there was no evidence to suggest that the safety or tolerability of frovatriptan was compromised, and thus no dosing changes have been recommended in the elderly.17 In addition, PK studies in subjects with (mild to severe) renal18 and (mild to moderate) hepatic impairment9 did not suggest that dosing adjustments were needed.
Frovatriptan has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins. It is unlikely that frovatriptan will affect the pharmacokinetics of concomitantly administered drugs, and it appears to have a low risk of interaction with other drugs, including propranolol, fluvoxamine, and ergotamine, which are often administered to migraine patients.13,19 Thus, dose adjustments are unlikely to be required when it is coadministered with other agents. Given the previous PK experience in special populations, the findings in this study in an adolescent population are not surprising.
Migraine headaches are a concern for the sizable minority of adolescents who suffer attacks, substantially affecting quality of life and productivity. Both the number and severity of migraines tend to be underestimated in adolescents, and treatment options are limited and often ineffective. There are currently 7 triptans marketed in the United States for adult migraineurs, and experience with this class of compounds is considerable. A number of studies and anecdotal reports support the use of triptans in adolescents; however, none are approved by the Food and Drug Administration for use in this population, and additional studies are needed to positively establish the role of triptans in the treatment of adolescents. In this study, the PK profile of a single 2.5-mg oral dose of frovatriptan in adolescents was essentially the same as in adults, and no safety or tolerability concerns about using frovatriptan in this age group arose.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSTUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication February 22, 2004; Revised version accepted June 6, 2004.
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REFERENCES |
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TOPABSTRACTSTUDY DESIGN AND STUDY...RESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Lewis DW. Migraine headaches in the adolescent. Adolesc Med. 2002;13: 413-432.[Medline] [Order article via Infotrieve]
2. Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KMA. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology. 2003;60: 1308-1312.
3. Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KMA. Headache and major depression: is the association specific to migraine? Neurology. 2000;54: 308-313.
4. Winner P, Rothner AD, Putnam DG, Asgharnejad M. Demographic and migraine characteristics of adolescents with migraine: Glaxo Wellcome clinical trials' database. Headache. 2003;43: 451-457.[Medline] [Order article via Infotrieve]
5. Wöber-Bingöl C, Wöber C, Wagner-Ennsgraber C, et al. IHS criteria for migraine and tension-type headache in children and adolescents. Headache. 1996;36: 231-238.[Medline] [Order article via Infotrieve]
6. Zambrino CA, Balottin U, Ferrari-Ginevra O, et al. Clinical characteristics of adolescent headache. Funct Neurol. 2000;15(suppl 3): 106-115.
7. Winner P. Triptans for migraine management in adolescents. Headache. 2002;42: 675-679.[Medline] [Order article via Infotrieve]
8. Winner P. Pediatric headaches: what's new? Curr Opin Neurol. 1999;12: 269-272.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Buchan P, Keywood C, Wade A, Ward C. Clinical pharmacokinetics of frovatriptan. Headache. 2002;42(suppl 2): S54-S62.
10. Jhee SS, Shiovitz T, Crawford AW, Cutler NR. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet. 2001;40: 189-205.[CrossRef][Medline] [Order article via Infotrieve]
11. Géraud G, Keywood C, Senard JM. Migraine headache recurrence: relationship to clinical, pharmacological, and pharmacokinetic properties of triptans. Headache. 2003;43: 376-388.[Medline] [Order article via Infotrieve]
12. Rapoport A, Ryan R, Goldstein J, Keywood C. Dose range-finding studies with frovatriptan in the acute treatment of migraine. Headache. 2002;42(suppl 2): S74-S83.
13. Buchan, P, Wade A, Ward C, Oliver SD, Stewart AJ, Freestone S. Frovatriptan: a review of drug-drug interactions. Headache. 2002;42(suppl 2): S63-S73.
14. Data on file, Vernalis Ltd.
15. Christensen ML, Mottern RK, Jabbour JT, Fuseau E. Pharmacokinetics of sumatriptan nasal spray in adolescents. J Clin Pharmacol. 2003;43: 721-726.
16. Christensen ML, Eades SK, Fuseau E, Kempsford RD, Phelps SJ, Hak LJ. Pharmacokinetics of naratriptan in adolescent subjects with a history of migraine. J Clin Pharmacol. 2001;41: 170-175.[Abstract]
17. Buchan P, Keywood C, Ward C. Pharmacokinetics of frovatriptan (VML 251/SB 209509) in healthy young and elderly male and female subjects [abstract P.52]. Cephalalgia. 1998;18: 410.
18. Cohen AF, van der Post J, Sacks S, Marsh J, Buchan P. Pharmacokinetics of frovatriptan in patients with renal impairment [abstract II-G1-33]. Cephalalgia. 1999;19: 365.
19. Buchan, P, Ward C, Stewart AJ, Freestone S. Frovatriptan has no clinically significant interactions with moclobemide, propranolol or ergotamine [abstract]. Headache. 2000;40: 402-403.
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